Article

Osthole induces human nasopharyngeal cancer cells apoptosis through Fas-Fas ligand and mitochondrial pathway

January 2018
Environmental Toxicology 33(10)

January 2018
33(10)

DOI:10.1002/tox.22530

Authors:

Dun-Cheng Chang

National Taichung University of Education

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Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. The present study investigated the activity of osthole in suppressing NPC along with the underlying mechanism. Cell growth inhibition was measured using the MTT assay. Apoptosis was detected through 4ʹ,6-diamidino-2-phenylindole staining and flow cytometry. Western blotting was used to identify the signaling pathway. Osthole markedly inhibited cell proliferation and induced apoptosis in the NPC cell line. Western blotting results revealed the increased activation of caspases 3, 8, and 9 and poly (ADP-ribose) polymerase. Osthole treatment significantly reduced the expression of the antiapoptotic protein Bcl-2 and increased the expression of the proapoptotic proteins Bax, Bak, BimL, BimS, and t-Bid. Osthole treatment also increased the expression of Fas, FADD, TNF-R1, TNF-R2, DcR2, RIP, and DR5. In addition, osthole treatment significantly increased the expression levels of phosphorylated ERK1/2 and JNK1/2. These results suggested that osthole exerts cytotoxic effects on NPC cell lines mainly through apoptosis mediated by the Fas–Fas ligand and mitochondrial pathway. Osthole could be a potential anticancer agent for NPC.

RETRACTED ARTICLE: Osthole sensitizes with radiotherapy to suppress tumorigenesis of human nasopharyngeal carcinoma in vitro and in vivo

Article

Full-text available

Nov 2018

Peng L, Huang YT, Chen J, et al. Cancer Manag Res. 2018;10:5471–5477. The Editor and Publisher of Cancer Management and Research wish to retract the published article. Concerns were raised regarding the alleged duplication of flow cytometry images in Figure 3. Specifically, The image for Figure 3A, Ctrl, appears to have regions of unexpected duplication with the image for Figure 3A, 2 Gy. The image for Figure 3A, 5 Gy, appears to have regions of unexpected duplication with the image for Figure 3A, Osthole. The authors agreed with the concerns that had been raised and provided data related to the study, however it was unable to verify the validity of the published work. Therefore, the decision was made to retract the article and the authors were notified of this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Effect of combined treatment with lobaplatin and osthole on inducing apoptosis and inhibiting proliferation in human breast cancer MDA-MB-231 cells

Article

Full-text available

Jan 2022
MED ONCOL

The present study investigates the underlying mechanisms of treatment with osthole (OST) combined with lobaplatin in human triple-negative MDA-MB-231 breast cancer cells. Human triple-negative MDA-MB-231 breast cancer cells were treated with different concentrations of OST (0.1, 1, 5, 10, 20, 50, and 100 μM) alone or in combination with 10 μM lobaplatin for 48 h. Cell viability was determined and compared between the treatment groups with the Cell Counting Kit-8 assay. Transcriptome sequencing (Project Number: M-GSGC0250521) was employed to elucidate the gene expression profile of the control group and the OST treatment group, and differentially expressed genes (DEGs) were identified based on the following criteria: log2FC > 0, P < 0.05. KEGG enrichment analysis was employed to determine the biological functions of these DEGs and the related signaling pathways. Finally, flow cytometry and western blotting were used to assess differences in the apoptosis rate and protein expression in MDA-MB-231 cells subjected to different treatments. The findings showed that OST inhibited the growth of MDA-MB-231 cells in a concentration-dependent manner and cell proliferation was significantly inhibited (as indicated by a decrease of 40%) at the OST concentration of 50 μM (P < 0.05). Transcriptome sequencing identified 4712 DEGs, including 2169 upregulated DEGs and 2543 downregulated DEGs. Enrichment analysis indicated that the DEGs played a role in apoptosis, p53 signaling, DNA replication, and cell cycle. In vitro experiments showed that OST and lobaplatin could significantly induce apoptosis in the MDA-MB-231 cells (P < 0.05), as indicated by elevation in the translation level of p53/Bax/caspase-3 p17 and downregulation of the Bcl-2 protein. Finally, combined treatment with OST and lobaplatin had an enhanced anti-tumor effect (P < 0.05) on proliferation and apoptosis, as well as more obvious effects on the related proteins (p53, Bax, Bcl-2, and caspase-3 p17). Thus, OST enhanced the apoptosis-mediated growth inhibitory effect of lobaplatin on breast cancer cells and has potential for the treatment of breast cancer in the future.

Osthole: an overview of its sources, biological activities, and modification development

Article

Full-text available

Oct 2021
MED CHEM RES

Osthole, also known as osthol, is a coumarin derivative found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. It can be obtained via extraction and separation from plants or total synthesis. Plenty of experiments have suggested that osthole exhibited multiple biological activities covering antitumor, anti-inflammatory, neuroprotective, osteogenic, cardiovascular protective, antimicrobial, and antiparasitic activities. In addition, there has been some research done on the optimization and modification of osthole. This article summarizes the comprehensive information regarding the sources and modification progress of osthole. It also introduces the up-to-date biological activities of osthole, which could be of great value for its use in future research.

Protective Effects of Osthole against Free Radical-Induced Hemolysis of Erythrocytes

Article

Full-text available

Oct 2020

Background: Osthole, one of the most active components of Cnidium monnieri, has different pharmacological and biological effects such as boosting the immune system, reducing rheumatoid pain, hepatoprotective, and inhibitory effect on osteoporosis. Furthermore, it showed anti inflammatory, anti-cancer, and antioxidant properties. However, there is little information about the antioxidant effects of osthole using cell-based assays. In the current work, we used in vitro model of 2,2-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced hemolysis of erythrocytes to investigate the protective effects of osthole against oxidative damage of biological membranes. Methods: Erythrocytes were challenged with 2, 2ꞌ-azobis (2-aminopropane) dihydrochloride (AAPH) as a model oxidant in the presence and absence of osthole. The protective effects of osthole on lipid peroxidation, protein carbonyl oxidation, glutathione (GSH) content of erythrocytes were evaluated and compared with control samples. Results: It was found that osthole has protective effects on erythrocyte hemolysis induced by AAPH at different concentrations in a time-dependent manner. Osthole also suppressed lipid and protein oxidation as well as reductions in GSH content in a concentration and timedependent manner. Conclusion: Osthole showed protective effects against free radical-induced hemolysis in rat erythrocytes. Therefore, it can be considered as a supplement for the prevention or treatment of a variety of human health problems associated with oxidative stress. However, further investigations are required to illustrate other possible impacts of osthole on cells.

Osthole enhances the immunosuppressive effects of bone marrow‐derived mesenchymal stem cells by promoting the Fas/FasL system

Article

Full-text available

Mar 2021
J CELL MOL MED

Thanks to the advantages of easy harvesting and escape from immune rejection, autologous bone marrow‐derived mesenchymal stem cells (BMSCs) are promising candidates for immunosuppressive therapy against inflammation and autoimmune diseases. However, the therapy is still challenging because the immunomodulatory properties of BMSCs are always impaired by immunopathogenesis in patients. Because of its reliable and extensive biological activities, osthole has received increased clinical attention. In this study, we found that BMSCs derived from osteoporosis donors were ineffective in cell therapy for experimental inflammatory colitis and osteoporosis. In vivo and in vitro tests showed that because of the down‐regulation of Fas and FasL expression, the ability of osteoporotic BMSCs to induce T‐cell apoptosis decreased. Through the application of osthole, we successfully restored the immunosuppressive ability of osteoporotic BMSCs and improved their treatment efficacy in experimental inflammatory colitis and osteoporosis. In addition, we found the immunomodulatory properties of BMSCs were enhanced after osthole pre‐treatment. In this study, our data highlight a new approach of pharmacological modification (ie osthole) to improve the immune regulatory performance of BMSCs from a healthy or inflammatory microenvironment. The development of targeted strategies to enhance immunosuppressive therapy using BMSCs may be significantly improved by these findings.

Osthole Inhibits Breast Cancer Progression through Upregulating Tumor Suppressor GNG7

Article

Full-text available

Feb 2021

Osthole (OST) is a plant-derived compound that can inhibit the proliferation of tumor cells and has a tumor-suppressive effect in multiple types of cancers. However, the mechanisms of OST-mediated breast cancer (BrCa) inhibition were still largely unknown. In this study, we made full use of the GSE85871 dataset to identify potential targets of OST in BrCa via multiple bioinformatics analysis. Next, a series of in vitro experiments were conducted to check the role of GNG7 in BrCa and the relationship between OST and GNG7. Through a series of bioinformatics analyses, GNG7 was identified as a potential target of OST, which could be significant upregulated by OST exposure in BrCa cells. Besides, GNG7 was lowly expressed in BrCa tissues compared with normal breast tissues, and BrCa patients with low GNG7 expression had shorter overall survival (OS) and relapse-free survival (RFS) compared with those with high GNG7 expression. Moreover, GNG7 silencing significantly enhanced cell proliferation and inhibited apoptosis, and exogenous overexpression of GNG7 showed reverse effects on BrCa cells. Last but not least, GNG7 inhibition could notably rescue OST-mediated cytotoxic effects. In summary, we identified GNG7 as a novel target for OST in BrCa and a potential tumor suppressor. Thus, OST could be therapeutically beneficial for BrCa through a GNG7-dependent mechanism.

Hydromethanolic root and aerial part extracts from Echium arenarium Guss suppress proliferation and induce apoptosis of multiple myeloma cells through mitochondrial pathway

Article

Full-text available

Jan 2021

Echium arenarium Guss is a Mediterranean plant traditionally used in healing skin wound and it was reported exhibiting potent antioxidant, antibacterial, and antiparasitic activities. However, antitumoral activities of this plant have not yet been explored. Here we investigated for the first time, root (EARE) and aerial part (EAAPE) extracts of E. arenarium Guss to examine cytotoxicity and apoptosis activation pathway on U266 human multiple myeloma (MM) cell line. We demonstrated that EARE and EAAPE decreased U266 cell viability in a dose dependent manner. Based on 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, EARE was significantly two times more efficient (IC50 value 41 μg/ml) than EAAPE (IC50 value 82 μg/ml) considering 48 h of treatment. Furthermore, after 24 h of exposure to 100 μg/ml of EARE or EAAPE, cell cycle showed remarkable increase in sub‐G1 population and a decrease of U266 cells proportion in G1 phase. In addition, EARE increased cell percentage in S phase. Moreover, analysis revealed that EAAPE or EARE induced apoptosis of U266 cells after 24 h of treatment. Interestingly, depolarization of mitochondrial membrane potential and activation of caspase 3/7 were demonstrated in treated U266 cells. Phytochemical analysis of E. arenarium extracts showed that EARE exhibited the highest content of total phenolic content. Interestingly, six phenolic compounds were identified. Myricitrin was the major compound in EARE, followed by luteolin 7‐O‐glucoside, resorcinol, polydatin, Trans‐hydroxycinnamic acid, and hyperoside. These findings proved that an intrinsic mitochondria‐mediated apoptosis pathway probably mediated the apoptotic effects of E. arenarium Guss extracts on U266 cells, and this will suggest several action plans to treat MM.

The combined usage of Matrine and Osthole inhibited endoplasmic reticulum apoptosis induced by PCV2

Preprint

Full-text available

May 2020

Background: Porcine circovirus type 2 (PCV2) is an important and common DNA virus that infect pig and can cause immunosuppression and induce apoptosis in the infected cells. To escape the host immune system, PCV2 constantly builds up complex mechanisms or mutates genes, and that is why it is difficult to eradicate complex PCV2 infection by relying on vaccines and single compound. At present, there is few literature reports on the effective prevention and treatment of PCV2 infection by a combination of two or more compounds. Previously, we have demonstrated the anti-PCV2 effect of Matrine in vitro, but its mechanism has not been further evaluated. Literatures have proven that Osthole has a variety of pharmacological activities, and we tested the ability of Osthole to inhibit PCV2 replication in cell culture. Therefore, this study explored the synergistic antiviral effect of Matrine combined with Osthole and their synergistic anti-apoptotic mechanism. Results: Osthole alone had an anti-PCV2 effect, and then its synergistic anti-PCV2 effect of Osthole and Matrine was better than that of Matrine or Osthole alone as demonstrated by qRT-PCR, IFA and Western blotting results. The anti-apoptotic mechanism of these two compounds by inducing the PERK pathway by PCV2 was elucidated through Annexin V-FITC/PI, JC-1 and Western blotting. Matrine and Osthole combination could inhibit the expression of Cap in Cap-transfected PK-15 cells, thus inhibiting Cap-induced PERK apoptosis. Ribavirin was used as a positive control. Conclusions: The combination of Osthole and Matrine had the synergistic effect of anti-PCV2 infection by directly inhibiting the expression of PCV2 Cap protein. The combination of these two compounds also inhibited PERK apoptosis induced by PCV2 Cap protein, possibly by regulating the level of GRP78. The results formed a base for further studies on the mechanism of anti-PCV2 in vivo using Matrine and Osthole combination and developing new anti-PCV2 compounds with Cap and GRP78 as therapeutic targets.

The combined usage of Matrine and Osthole inhibited endoplasmic reticulum apoptosis induced by PCV2

Preprint

Full-text available

May 2020

The combined usage of Matrine and Osthole inhibited endoplasmic reticulum apoptosis induced by PCV2

Article

Full-text available

Oct 2020
BMC MICROBIOL

Background Porcine circovirus type 2 (PCV2) is an important and common DNA virus that infect pig and can cause immunosuppression and induce apoptosis in the infected cells. To escape the host immune system, PCV2 constantly builds up complex mechanisms or mutates genes, and that is why it is difficult to eradicate complex PCV2 infection by relying on vaccines and single compound. At present, there is few literature reports on the effective prevention and treatment of PCV2 infection by a combination of two or more compounds. Previously, we have demonstrated the anti-PCV2 effect of Matrine in vitro, but its mechanism has not been further evaluated. Literatures have proven that Osthole has a variety of pharmacological activities, and we tested the ability of Osthole to inhibit PCV2 replication in cell culture. Therefore, this study explored the synergistic antiviral effect of Matrine combined with Osthole and their synergistic anti-apoptotic mechanism. Results Osthole alone had an anti-PCV2 effect, and then its synergistic anti-PCV2 effect of Osthole and Matrine was better than that of Matrine or Osthole alone as demonstrated by qRT-PCR, IFA and Western blotting results. The anti-apoptotic mechanism of these two compounds by inducing the PERK pathway by PCV2 was elucidated through Annexin V-FITC/PI, JC-1 and Western blotting. Matrine and Osthole combination could inhibit the expression of Cap in Cap-transfected PK-15 cells, thus inhibiting Cap-induced PERK apoptosis. Ribavirin was used as a positive control. Conclusions The combination of Osthole and Matrine had the synergistic effect of anti-PCV2 infection by directly inhibiting the expression of PCV2 Cap protein. The combination of these two compounds also inhibited PERK apoptosis induced by PCV2 Cap protein, possibly by regulating the level of GRP78. The results formed a base for further studies on the mechanism of anti-PCV2 in vivo using Matrine and Osthole combination and developing new anti-PCV2 compounds with Cap and GRP78 as therapeutic targets.

The combined usage of Matrine and Osthole inhibited endoplasmic reticulum apoptosis induced by PCV2

Preprint

Full-text available

May 2020

Background: Porcine circovirus type 2 (PCV2) is an important DNA pathogen commonly in pig farms, which can cause immunosuppression and induce apoptosis. To evade clearance by the host immune system, PCV2 constantly builds up complex mechanisms or mutates genes, it is difficult to eradicate complex PCV2 infection by relying on vaccine immunity and one compound. At present, there is no literature report on the effective prevention and treatment of PCV2 infection by the combined a of two or more compounds through multiple pathways and multiple targets. We have previously demonstrated the anti-PCV2 effect of Matrine in vitro, but its mechanism has not been further studied. Many literatures have proved that Osthole has a variety of pharmacological activities. Therefore, this study explored the synergistic antiviral effect of Matrine combined with Osthole and the synergistic anti-apoptosis mechanism in the same pathway and targets. Results: It was first demonstrated that Osthole alone had anti-PCV2 effect and the synergistic anti-PCV2 effect combined with Matrine was better than Matrine and Osthole alone by qPCR, IFA and Western blot results. Subsequently, demonstrated that the reduction of endoplasmic reticulum PERK apoptosis induced by PCV2 was mainly contributed the mechanism of anti-PCV2 using these two extracts by Annexin V-FITC/PI, JC-1 and Western blot results. Finally, it was further demonstrated that Matrine combined with Osthole could inhibit the expression of Cap in cap-transfected PK-15 cells, thus inhibiting Cap-induced PERK apoptosis. In this study, Ribavirin was used as the positive control. Conclusions: It was proved that the synergistic anti-PCV2 effect of Matrine combined with Osthole was significantly better than that of Matrine and Osthole alone. And the two ombined, with Cap and GRP78 as potential targets of anti-PCV2, further inhibited PERK apoptosis induced by PCV2 infection by directly inhibiting the expression of PCV2 Cap protein. The results formed a basis for further studies on the mechanism of anti-PCV2 in vivo using Matrine combined with Osthole and developing new anti-PCV2 compounds with Cap and GRP78 as therapeutic targets.

Anti-Tumor Effects of Osthole in Different Malignant Tissues: A Review of Molecular Mechanisms

Article

Feb 2020

Cancer management and/or treatment requires a comprehensive understanding of the molecular and signaling pathways involved. Recently, much attention has been directed to these molecular and signaling pathways, and it has been suggested that a number of biomolecules/players involved in such pathways, such as PI3K/Akt, NF-κB, STAT, and Nrf2 contribute to the progression, invasion, proliferation, and metastasis of malignant cells. Synthetic anti-tumor agents and chemotherapeutic drugs have been a mainstay in cancer therapy and are widely used to suppress the progression and, hopefully, halt the proliferation of malignant cells. However, these agents have some undesirable side-effects and, therefore, naturally-occurring compounds with high potency and fewer side-effects are now of great interest. Osthole is a plant-derived chemical compound that can inhibit the proliferation of malignant cells and provide potent anti-cancer effects in various tissues. Therefore, in this review, we present the main findings concerning the potential anti-tumor effects of osthole and its derivatives and describe possible molecular mechanisms by which osthole may suppress malignant cell proliferation in different tissues.

Osthole: A Multifunctional Natural Compound with Potential Anticancer, Antioxidant and Anti-inflammatory Activities

Article

Jan 2020
MINI-REV MED CHEM

Nature has always proved to be a significant reservoir of bioactive scaffolds which have been used for the discovery of drugs since times. Medicinal plants continue to be a solid niche for biologically active and therapeutically effective chemical entities, opening up new avenues for the successful treatment of several human diseases. Contribution of plant-derived compounds either in their original or semi-synthetic derivative forms extends far back in time in drug discovery. This review aims to focus on the sources, biological, and pharmacological profile of a pharmacologically active plant-derived coumarin, osthole, which is an important component of numerous remedial plants such as Cnidium monnieri. Several studies have revealed that osthole possess pharmacological properties such as anticancer, antioxidant, anti-hyperglycemic, neuroprotective, and antiplatelet. Osthole has been reported to regulate various signaling pathways which in turn modulate several apoptosis related proteins, cell cycle regulators, protein kinases, transcriptional factors, cytokines, and growth receptors affiliated with inflammation, proliferation and several other ailments. Osthole is known to halt proliferation and metastasis of cancerous cells by arresting the cell cycle and inducing apoptosis. The data in this review paper supports the pharmacological potential of osthole but further experimentation, biosafety profiling and synergistic effects of this compound need to be focused by the researchers to understand the full spectrum of pharmacological potential of this therapeutically potent compound.

Effects of osthol on activity, mRNA and protein expression of Cyp3a in rats in vivo

Article

Jan 2020

Osthol (OST) has a wide range of pharmacological effects and has long been used in clinical medicine in China. Previous studies have indicated that OST has weak inhibitory effects on CYP3A4 in human liver microsomes. The aim of the present study was to investigate the inhibition of Cyp3a by OST in rats in vivo. A substrate assay was used to corroborate the inhibitory effect on Cyp3a by OST in rats, and the substrate probe (midazolam) was detected by high‐performance liquid chromatography (HPLC). Semi‐quantitative RT‐PCR (SqRT‐PCR) analysis was used to study the effect of OST on Cyp3a1 and Cyp3a2 mRNA expression and Western blot analysis was used to investigate the effect of OST on Cyp3a1 and Cyp3a2 protein expression. Our study confirmed the inhibitory effect of OST on Cyp3a and indicated that the inhibitory effect on Cyp3a was stronger in the group receiving multiple doses compared to the single dose group. SqRT‐PCR analysis results showed that medium and high doses of OST (20, and 40 mg/kg, respectively) had inhibitory effect on Cyp3a1 mRNA expression but not on Cyp3a2 mRNA expression. Western blot analysis results indicated that the inhibitory effect of the medium, high OST doses on Cyp3a1 and Cyp3a2 protein expression was significantly different. We also demonstrated that the inhibitory effect of OST on Cyp3a in rats resulted from the comprehensive effect of the direct inhibition of the Cyp3a enzyme, as well as the down‐regulation of its mRNA and protein expression level.

RIPK3 mediates renal tubular epithelial cell apoptosis in endotoxin‑induced acute kidney injury

Article

Full-text available

Jun 2019

Renal tubular epithelial cell apoptosis is an important pathological mechanism of septic acute kidney injury (AKI). Endotoxin, also known as lipopolysaccharide (LPS), has a key role in septic AKI and can directly induce tubular epithelial cell apoptosis. The upregulation of receptor‑interacting protein kinase 3 (RIPK3) in tubular epithelial cells has been reported in septic AKI, with RIPK3 mediating apoptosis in several cell types. In the present study, the effect of RIPK3 on endotoxin‑induced AKI was investigated in mouse tubular epithelial cell apoptosis in vitro and in vivo. It was found that the expression of RIPK3 was markedly increased in endotoxin‑induced AKI. Endotoxin‑induced AKI and tubular epithelial cell apoptosis could be attenuated by GSK'872, a RIPK3 inhibitor. LPS stimulation also upregulated RIPK3 expression in tubular epithelial cells in a time‑dependent manner. Both RIPK3 inhibitor and small interfering RNA (siRNA) targeting RIPK3 reduced LPS‑induced tubular epithelial cell apoptosis in vitro. The expression of the proapoptotic protein Bax was induced by LPS and reversed by GSK'872 or RIPK3‑siRNA. The present study revealed that RIPK3 mediated renal tubular cell apoptosis in endotoxin‑induced AKI. RIPK3 may be a potential target for the prevention of renal tubular cell apoptosis in endotoxin‑induced AKI.

Polarization of Tumor-Associated Macrophages by Chinese Medicine Intervention: Mechanisms and Applications

Chapter

Full-text available

May 2019

Osthole inhibits pancreatic cancer progression by directly exerting negative effects on cancer cells and attenuating tumor-infiltrating M2 macrophages

Article

Full-text available

Jul 2018

Pancreatic cancer has remained a major cause of cancer-related deaths. A hallmark of pancreatic cancer is extensive stromal reactions, resulting in a unique tumor microenvironment, especially the involvement of macrophages. These tumor-educated cells limit the efficacy of chemotherapy. Therefore, it is necessary to identify an effective treatment strategy. In this study, we aimed to explore the anti-tumor and immunomodulatory effects of osthole on pancreatic cancer. We found that osthole suppressed Panc 02 cell migration and proliferation and induced apoptosis as shown in vitro. Osthole also attenuated the development of pancreatic cancer in mice by inhibiting tumor-infiltrating M2 macrophages in our study. Additionally, osthole inhibited the polarization of primary bone marrow cells into M2 macrophages and inhibited the expression of MRC1, CCL22 and TGF-β in the M2 polarization process in vitro. Detection of the related signaling pathways revealed that osthole exerted immunomodulatory effects on M2 macrophages by down-regulating p-STAT6 and the p-ERK1/2-C/EBP β axis. These results indicated that osthole has effective anti-tumor and immunomodulatory effects on pancreatic cancer.

Osthole improves collagen-induced arthritis in a rat model through inhibiting inflammation and cellular stress

Article

Full-text available

Dec 2018

Background Osthole is a natural product that has multiple bioactive functions and has been reported to exert potent immunosuppressive effects. However, the therapeutic effect of osthole on arthritis has not been explored. In the present study, a collagen-induced arthritis rat model, IL-1β-stimulated SW982 cells, and RA-like fibroblast-like synoviocytes (FLS) were employed to investigate the effect and possible mechanism of osthole on arthritis in vivo and in vitro. Results 20 and 40 mg/kg osthole significantly alleviated collagen-induced arthritic symptoms based on histopathology and clinical arthritis scores, and improved erosion using HE staining. 20 and 40 mg/kg osthole decreased the level of IL-1β, TNF-α and IL-6 in rats and ameliorated oxidative stress in serum evaluated using ELISA kits. In addition, treatment with 50 and 100 μM osthole for 48 h inhibited 10 ng/ml IL-1β-stimulated proliferation and migration of SW982, and significantly inhibited the expression of matrix metalloproteinases, such as MMP-1, MMP-3 and MMP-13, as detected by western blot. 50 and 100 μM osthole also blocked the generation of IL-6 and TNF-α in IL-1β-stimulated SW982 cells. The NF-κB and MAPK pathways were also inhibited by osthole in IL-1β-treated SW982 cells. Conclusion These results collectively demonstrated that osthole improves collagen-induced arthritis in a rat model and IL-1β-treated SW982 cells through inhibiting inflammation and cellular stress in vivo and in vitro, and osthole might be a promising therapeutic agent for RA.

Osthole: A Medicinally Privileged Natural Compound with its Therapeutic Potential

Article

Oct 2023

Osthole is a coumarin derived natural compound which is an essential ingredient of Traditional Chinese Medicine (TMC) which is widely distributed in nature in plants like Cnidium monnieri (L) Cusson and Angelica pubescens. Current study presents a critical review on description of pharmacological importance of osthole, which is reported to exhibit anticancer, antioxidant, osteogenic, hepatoprotective, neuroprotective, cardiovascular protective, antimicrobial, immuno-modulatory and inflammatory activities. Till date, the reports include pharmacological properties, brief chemistry or on advanced methods to explore osthole content in variety of plants. Present review seeks to highlight the sources, biosynthesis, extraction methods, pharmacological properties of the molecule and its derivatives. A brief discussion on patents recently published and granted on the molecule has also been highlighted. Thus the overview of the literature presents the analysis about future possible modalities of the research on this molecule.

An Overview on Sources, Biosynthesis and Bioactivities of Osthole: A Potential Bioactive Compound

Article

Oct 2023

Different plants are rich in medicinal properties, which nature has provided in abundance for the living beings of this earth. Since the dawn of time, nature has proven to be a rich source of bioactive scaffolds that have been exploited in the creation of pharmaceuticals. Osthole is a natural coumarin derivative and potential bioactive compound found in plants. Herein, we aimed to review the origins, biology and pharmacological profiles of osthole, a plant-derived coumarin that is found in a variety of therapeutic plants, including Cnidium monnieri. Osthole, also called 7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one, is a naturally occurring coumarin found to be present in different plants of the Apiaceae family, i.e., Cnidium monnieri and Angelica pubescens. The biological potential of the osthole in medicine has been investigated using a variety of literature databases. This study gathered diverse scientific research data on osthole from various literature sources and analysed, including Scopus, Google Scholar, Web of Science and PubMed. From the collected data, it was found that osthole have potential pharmacological activities, such as anticancer, antioxidant, osteogenic, cardioprotective, antimicrobial, antiparasitic, anti-hyperglycaemic, neuroprotective, and antiplatelet. The data in this review paper supports the pharmacological potential of osthole, but to completely appreciate the pharmacological potential of this therapeutically powerful chemical, researchers must focus their efforts on further experimentation, biosafety profiling and synergistic effects of this compound. The purpose of this study was to learn more about the origins, biology, and therapeutic benefits of osthole in medicine in order to develop better treatments for human diseases.

Matrine combined with Osthole inhibited the PERK apoptosis of splenic lymphocytes in PCV2-infected mice model

Article

Full-text available

Jan 2023
BMC Vet Res

Background Porcine circovirus type 2 (PCV2) is one of the major pathogens commonly found in pigs, which causes immunosuppression and apoptosis. Vaccination and a single drug cannot totally prevent and treat PCV2 infection. Our previous in vitro study reported that the synergistic anti-PCV2 effect of Matrine and Osthole was better than that of Matrine or Osthole alone, This study was aimed to evaluate the synergistic anti-PCV2 effect as well as the underline molecular mechanism of Matrine and Osthole in Kunming (KM) mice model infected with PCV2. KM mice were randomly divided into 8 groups namely control group, PCV2 infected, Matrine combined with Osthole high dose treatment (40 mg/kg + 12 mg/kg), medium dose treatment (20 mg/kg + 6 mg/kg), low dose treatment (10 mg/kg + 3 mg/kg), Matrine treatment (40 mg/kg), Osthole treatment (12 mg/kg) and Ribavirin positive control (40 mg/kg) groups. PCV2 was intraperitoneally (i.p.) injected in all mice except the control group. 5 days of post-infection (dpi), mice in different treatment groups were injected i.p. with various doses of Matrine, Osthole and Ribavirin once daily for the next 5 consecutive days. Results The synergistic inhibitory effect of Matrine and Osthole on PCV2 replication in mouse liver was significantly heigher than that of Matrine and Osthole alone. The expression of GRP78, p-PERK, p-eIF2α, ATF4, CHOP, cleaved caspase-3 and Bax proteins were significantly reduced, while that of Bcl-2 was significantly increased in Matrine combined with Osthole groups, which alleviated the pathological changes caused by PCV2, such as interstitial pneumonia, loss of spleen lymphocytes, infiltration of macrophages and eosinophils. Conclusions The synergistic anti-apoptotic effect of Matrine and Osthole was better than their alone effect, Both Matrine and Osthole had directly inhibited the expression of PCV2 Cap and the apoptosis of spleen cells induced by PCV2 Cap through the PERK pathway activated by endoplasmic reticulum (ER) GRP78. These results provided a new insight to control PCV2 infection and provide good component prescription candidate for the development of novel anti-PCV2 drugs.

Osthole: Synthesis, Structural Modifications and Biological Properties

Article

Feb 2022
MINI-REV MED CHEM

Osthole, a naturally occurring coumarin-type compound, is isolated from a Chinese herbal medicine Cnidium monnieri (L.), and exhibits a broad range of biological properties. In this review, the total synthesis and structural modifications of osthole and its analogs are described. Additionally, the progress on bioactivities of osthole and its analogs is outlined since 2016. Moreover, the structure-activity relationships and mechanisms of action of osthole and its derivatives are discussed. These can provide references for future design, development and application of osthole and its analogs as drugs or pesticides in the fields of medicine and agriculture.

A novel sight of the primary active compounds from Umbelliferae: focusing on mitochondria

Article

Full-text available

Feb 2022
MED CHEM RES

Mitochondria perform diverse interconnected functions, participating in energy metabolism, oxidative stress, calcium hemostasis, and apoptosis. It is therefore not surprising that mitochondria have emerged as a key factor in a series of chronic diseases, including metabolic diseases, cerebro-cardiovascular diseases, neurodegenerative diseases, and cancer, which are regarded as the new global health challenge. The family Umbelliferae enjoys an important medicinal status. Given the growing body of evidence about the close connection between Chinese herbs from the family Umbelliferae and mitochondria-related diseases, more attention is paid to elucidate the role of mitochondria in it. The review generalizes three classes of active compounds of Umbelliferae taking ten commonly-used herbs as an example, they are coumarins, phthalides, and phenolic acids respectively. Moreover, when it comes to the underlying mechanisms of these compounds to mitochondria-related diseases, we highlight the change of mitochondria-related enzymes, regulatory proteins, ions, signaling molecules, and so on. In conclusion, we propose a promising drug-designing strategy, mitochondria-targeted drugs referring to natural compounds of Umbelliferae that themselves are able to improve the mitochondrial environment.

Osthole induces necroptosis via ROS overproduction in glioma cells

Article

Full-text available

Jan 2021

Glioma is a common primary malignant tumor that has poor prognosis and often develops drug resistance. The coumarin derivative osthole has previously been reported to induce cancer cell apoptosis. Recently, we found that it could also trigger glioma cell necroptosis, a type of cell death which is usually accompanied with reactive oxygen species (ROS) production. However, the relationship between ROS production and necroptosis induced by osthole has not been fully elucidated. In this study, we found that osthole could induce necroptosis of glioma cell lines U87 and C6; such cell death was distinct from apoptosis induced by MG‐132. Expression of necroptosis inhibitor caspase‐8 was decreased and levels of necroptosis proteins RIP1, RIP3 and MLKL were increased in U87 and C6 cells after treatment with osthole, while levels of apoptosis‐related proteins caspase‐3, caspase‐7 and caspase‐9 were not increased. Lactate dehydrogenase (LDH) release and flow cytometry assays confirmed that cell death induced by osthole was primarily necrosis. In addition, necroptosis induced by osthole was accompanied by excessive production of ROS, as observed for other necroptosis‐inducing reagents. Pretreatment with the RIP1 inhibitor Necrostatin‐1 (Nec‐1) attenuated both osthole‐induced necroptosis and the production of ROS in U87 cells. Furthermore, the ROS inhibitor N‐acetyl‐L‐cysteine (NAC) decreased osthole‐induced necroptosis and growth inhibition. Overall, these findings suggest that osthole induces necroptosis of glioma cells via ROS production, and thus may have potential for development into a therapeutic drug for glioma therapy.

Coumarins modulate the anti-glioma properties of temozolomide

Article

Full-text available

May 2020
EUR J PHARMACOL

In the recent years, coumarin bioactive compounds have been identified to posess anticancer properties. Therefore, the aim of the present study was to investigate for the first time the efficacy of osthole, umbelliferone, esculin, and 4-hydroxycoumarin, alone and in combination with Temozolomide, in the elimination of deadly brain tumors, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) cells via programmed death. Our results indicated that osthole, umbelliferone, esculin, and 4-hydroxycoumarin initiated mainly apoptosis in the T98G and MOGGCCM cells. Osthole was the most effective. It also initiated autophagy in a small percentage of the cell population. The co-incubation with Temozolomide did not increase the pro-apoptotic potential of natural compounds but decreased the level of autophagy in the T98G cells. Apoptosis was associated with reduced mitochondrial membrane potential, activation of caspase 3, inhibition of Bcl-2 expression and the presence of a Bcl-2/Beclin 1. Blocking of Bcl-2 expression resulted in promotion of apoptosis, but not autophagy, in the MOGGCCM and T98G lines. It also sensitized astrocytoma cells, but not GBM, to the combined osthole and TMZ treatment, which was correlated with a reduced level of Beclin 1 and increased expression of caspase 3. Osthole and TMZ, alone and in combination, inhibited the migratory phenotype of the GBM and AA cells. In summary, our results indicated that osthole effectively eliminated glioma cells via apoptosis, what was correlated with Bcl-2/Beclin 1 complex formation. Considering the anti-migratory effect, osthole and Temozolomide display antiglioma potential but it needs further extensive studies.

Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins with Anticancer Effects

Article

Full-text available

Mar 2020

Coumarins are the seconder metabolites of some plants, fungi, and bacteria. Coumarins and the hybrid molecules of coumarins are the compounds which have been widely studied for their anticancer effects. They belong to benzopyrone chemical class, more precisely benzo-α-pyrones, where benzene ring is fused to pyrone ring. In nature, coumarins are found in higher plants like Rutaceae and Umbelliferae and some essential oils like cinnamon bark oil, cassia leaf oil and lavender oil are also rich in coumarins. The six main classes of coumarins are furanocoumarins, dihydrofuranocoumarins, pyrano coumarins, pyrone substituted coumarins, phenylcoumarins and bicoumarins. As well as their wide range of biological activities, coumarins and the hybrid molecules of coumarins are proven to have an important role in anticancer drug development due to the fact that many of its derivatives have shown an anticancer activity on various cell lines. Osthol, imperatorin, esculetin, scopoletin, umbelliprenin, angelicine, bergamottin, limettin, metoxhalen, aurapten and isopimpinellin are some of these coumarins. This review summarizes the anticancer effects of coumarins and their hybrid molecules including the novel pharmaceutical formulations adding further information on the topic for the last ten years and basically focusing on the structure-activity relationship of these compounds in cancer.

Osthole alleviates oxidized low-density lipoprotein-induced vascular endothelial injury through suppression of transforming growth factor-β1/Smad pathway

Article

Dec 2018
INT IMMUNOPHARMACOL

Osthole, a naturally-derived coumarin, has been shown to exhibit pharmacological activities including anti-inflammatory, anti-oxidative and cardiovascular protective effects. However, the effect of osthole on oxidized low-density lipoprotein (ox-LDL)-induced endothelial injury and its underlying mechanism remain unknown. We found that osthole did not affect viability of human umbilical vein endothelial cells (HUVECs) but alleviated ox-LDL-induced cytotoxicity in HUVECs. Osthole repressed ox-LDL-induced release of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in HUVECs. Osthole reversed ox-LDL-induced elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) level, and reduction of superoxide dismutase (SOD) activity in HUVECs. Meanwhile, osthole attenuated ox-LDL-induced increase of mRNA expression and secretion of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Osthole increased nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation in ox-LDL-treated HUVECs. Furthermore, osthole inhibited ox-LDL-induced activation of the transforming growth factor-β1 (TGF-β1)/Smad pathway and activation of TGF-β1/Smad pathway by TGF-β1 attenuated the protective effects of osthole on HUVECs injury. These results suggested that osthole attenuated ox-LDL-induced HUVECs injury by inhibiting the TGF-β1/Smad pathway, suggesting that osthole might be a promising therapeutic agent for the treatment of atherosclerosis.

Effectiveness of Osthole on Uric Acid Crystal-induced Acute Gouty Arthritis Through the Inhibition of NLRP3 Inflammasome

Article

Aug 2018

Background and Objective: Inflammation is a key factor in the pathogenesis of arthritis. In the present study, investigated the potential of osthole, a major natural product, to treat monosodium urate crystal (MSU) induced acute gouty arthritis in rats and explore the mechanisms underlying osthole mediated immunomodulation. Materials and Methods: Rats were oral administrated with osthole at 24 h prior to 3 mg MSU injection, the volume and width of swelling ankle were recorded to evaluate the protection of osthole in vivo. LPS+MSU in Raw 264.7 cells was utilized to assess the effects of osthole on NLRP3 inflammasome in vitro. Results: Osthole could alleviate MSU-induced arthritis through inhibiting the generation of inflammatory factors and NLRP3 inflammasome activation in vivo. Pretreatment with osthole significantly suppressed MSU or LPS induced NF-κB signal along with the transcription of inflammatory factors. In addition, osthole decreased MSU induced oxidative stress and lysosomal damage. Current findings illustrated that osthole significantly suppressed NLRP3 inflammasome in synovial tissue and macrophage cells. The potential mechanism may be based on the attenuation of NF-κB mediated first signal and oxidative stress and lysosome mediated second signal in NLRP3 inflammasome activation. Conclusion: Osthole might be a promising therapeutic agent for alleviating gouty arthritis through inhibiting NLRP3 inflammasome.

Tetrandrine Induces Apoptosis of Human Nasopharyngeal Carcinoma NPC-TW 076 Cells through Reactive Oxygen Species Accompanied by an Endoplasmic Reticulum Stress Signaling Pathway

Article

Full-text available

Oct 2016
MOLECULES

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy of the head and neck and the incidence is higher in Southeast Asia. Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid, a natural product, and exhibits biological activities including action against many human cancer cell lines. However, the molecular mechanism of TET-induced cell apoptosis in human NPC cells is still unclear. In the present study, we investigated TET-induced apoptotic cell death and associated possible signal pathways on human nasopharyngeal carcinoma NPC-TW 076 cells in vitro. Phase contrast microscopy was used to examine cell morphology and DAPI staining was used to examine chromatin condensation. Flow cytometry assay was used to measure total viable cells, cell cycle and sub-G1 phase distribution, reactive oxygen species (ROS), Ca²⁺, and mitochondria membrane potential (DYm) in NPC-TW 076 cells. Results indicate that TET induced cell death through the cell morphological changes, caused G0/G1 phase arrest, increased ROS and Ca²⁺ production, and finally caused apoptotic cell death in NPC-TW 076 cells. There was no influence on the level of δψm after TET treatment. Western blotting indicated that TET increased endoplasmic reticulum (ER) stress associated protein expression such as GADD153, GRP78, ATF-6α and ATF-6 βwhich indicated that TET induced cell death through ER stress. ER stress is a potential target in cancer treatment, so the ability of TET to induce ER stress response and to activate programming cell death in NPC-TW 076 cells make this molecule become a promising anticancer agent.

Osthole induces lung cancer cell apoptosis through inhibition of inhibitor of apoptosis family proteins

Article

Full-text available

Sep 2016

In the present study, we investigated the effects and mechanisms of Osthole on the apoptosis of non-small cell lung cancer (NSCLC) cells and its synergistic effect with Embelin. Our results revealed that treatment with both Osthole and Embelin inhibited cell proliferation. Notably, combination treatment of Osthole and Embelin inhibited cell proliferation more significantly compared with monotherapy. In addition, morphological analysis and Annexin V/propidium iodide analysis revealed that the combination of Osthole and Embelin enhanced their effect on cell apoptosis. We further examined the effect of Osthole on the expression of inhibitor of apoptosis protein (IAP) family proteins. That treatment of A549 lung cancer cells with various concentrations of Osthole was observed to decrease the protein expression of X-chromosome-encoded IAP, c-IAP1, c-IAP2 and Survivin, and increase Smac expression in a dose-dependent manner. Furthermore, it was noted that Osthole or Embelin alone increased the expression of BAX, caspase-3, caspase-9, cleaved caspase-3 and cleaved caspase-9, and decreased Bcl-2 levels following treatment. Osthole and Embelin combination treatment had a synergistic effect on the regulation of these proteins. In conclusion, our study demonstrated that Osthole inhibited proliferation and induced the apoptosis of lung cancer cells via IAP family proteins in a dose-dependent manner. Osthole enhances the antitumor effect of Embelin, indicating that combination of Osthole and Embelin has potential clinical significance in the treatment of NSCLC.

Potential role of oxidative stress-induced apoptosis in mediating chromosomal rearrangements in nasopharyngeal carcinoma

Article

Full-text available

Dec 2016

Background Genetic aberrations have been identified in nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains elusive. There are increasing evidences that the apoptotic nuclease caspase-activated deoxyribonuclease (CAD) is one of the players leading to translocation in leukemia. Oxidative stress, which has been strongly implicated in carcinogenesis, is a potent apoptotic inducer. Most of the NPC etiological factors are known to induce oxidative stress. Although apoptosis is a cell death process, cells possess the potential to survive apoptosis upon DNA repair. Eventually, the surviving cells may carry rearranged chromosomes. We hypothesized that oxidative stress-induced apoptosis may cause chromosomal breaks mediated by CAD. Upon erroneous DNA repair, cells that survive apoptosis may harbor chromosomal rearrangements contributing to NPC pathogenesis. This study focused on the AF9 gene at 9p22, a common deletion region in NPC. We aimed to propose a possible model for molecular mechanism underlying the chromosomal rearrangements in NPC. Results In the present study, we showed that hydrogen peroxide (H2O2) induced apoptosis in NPC (HK1) and normal nasopharyngeal epithelial (NP69) cells, as evaluated by flow cytometric analyses. Activity of caspases 3/7 was detected in H2O2-treated cells. This activity was inhibited by caspase inhibitor (CI). By nested inverse polymerase chain reaction (IPCR), we demonstrated that oxidative stress-induced apoptosis in HK1 and NP69 cells resulted in cleavages within the breakpoint cluster region (BCR) of the AF9 gene. The gene cleavage frequency detected in the H2O2-treated cells was found to be significantly higher than untreated control. We further found that treatment with CI, which indirectly inhibits CAD, significantly reduced the chromosomal breaks in H2O2-cotreated cells. Intriguingly, a few breakpoints were mapped within the AF9 region that was previously reported to translocate with the mixed lineage leukemia (MLL) gene in acute lymphoblastic leukemia (ALL) patient. Conclusions In conclusion, our findings suggested that oxidative stress-induced apoptosis could be one of the mechanisms underlying the chromosomal rearrangements in NPC. CAD may play an important role in chromosomal cleavages mediated by oxidative stress-induced apoptosis. A potential model for oxidative stress-induced apoptosis mediating chromosomal rearrangements in NPC is proposed.

Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts

Article

Full-text available

Jan 2016

Morphine is an opioid analgesic drug often used for pain relief in cancer patients. However, there is growing evidence that morphine may modulate tumor growth, progression and metastasis. In this study, we evaluated whether morphine modulates cisplatin-induced apoptosis in human nasopharyngeal carcinoma CNE-2 cells and whether morphine affects the antitumor activity of cisplatin on tumor growth in human nasopharyngeal carcinoma CNE-2 xenografts in nude mice. We showed that a pretreatment with morphine (1μg/ml) inhibited the sensitivity of CNE-2 cells to cisplatin by inhibiting cisplatin-induced CNE-2 cell apoptosis, decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. However, a high dose of morphine (1000μg/ml) had the opposite effect. We also showed that at a low dose, morphine enhances chemoresistance in an in vivo nasopharyngeal carcinoma (NPC) model by inhibiting cisplatin-induced apoptosis and decreasing neovascularization. Taken together, our results indicate that a low dose of morphine may lead to chemoresistance of cisplatin in NPC models in vitro and in vivo by inhibiting cisplatin-induced apoptosis and decreasing neovascularization.

Oncogenic role of the TP53-induced glycolysis and apoptosis regulator in nasopharyngeal carcinoma through NF-κB pathway modulation

Article

Full-text available

Dec 2015
INT J ONCOL

The TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target gene, which functions to suppress reactive oxygen species (ROS) damage and protect cells from apoptosis. In this study, we investigated the role of TIGAR in nasopharyngeal carcinoma (NPC) tumorigenesis. Imnunohistochemical analysis of the tissue specimens from nasopharyngeal carcinoma patients showed a higher expression level of TIGAR in tumor tissues, compared with normal nasopharyngeal epithelium. Knockdown of TIGAR by lentivirus-shRNA in CNE-2 or 5-8F cells resulted in decreased cell growth, colony formation, migration, invasion, and induced apoptosis. TIGAR overexpression exerted the opposite effects except for apoptosis reduction. In the xenograft tumor models, TIGAR knockdown reduced tumor growth rate and weight, whereas TIGAR overexpression showed the opposite effects. In addition, the NF-κB signaling pathway was decreased in TIGAR silenced cells. In conclusion, our data demonstrated that TIGAR acted as an oncogene in NPC tumorigenesis, and knockdown of TIGAR inhibited NPC tumor growth through the NF-κB pathway.

Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine

Article

Full-text available

Jul 2015
EVID-BASED COMPL ALT

This paper reviews the latest understanding of biological and pharmacological properties of osthole (7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one), a natural product found in several medicinal plants such as Cnidium monnieri and Angelica pubescens . In vitro and in vivo experimental results have revealed that osthole demonstrates multiple pharmacological actions including neuroprotective, osteogenic, immunomodulatory, anticancer, hepatoprotective, cardiovascular protective, and antimicrobial activities. In addition, pharmacokinetic studies showed osthole uptake and utilization are fast and efficient in body. Moreover, the mechanisms of multiple pharmacological activities of osthole are very likely related to the modulatory effect on cyclic adenosine monophosphate (cAMP) and cyclic adenosine monophosphate (cGMP) level, though some mechanisms remain unclear. This review aims to summarize the pharmacological properties of osthole and give an overview of the underlying mechanisms, which showcase its potential as a multitarget alternative medicine.

Osthole inhibits proliferation of human breast cancer cells by inducing cell cycle arrest and apoptosis

Article

Full-text available

Apr 2015

Recent studies have revealed that osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, a traditional Chinese medicine, possesses anticancer activity. However, its effect on breast cancer cells so far has not been elucidated clearly. In the present study, we evaluated the effects of osthole on the proliferation, cell cycle and apoptosis of human breast cancer cells MDA-MB 435. We demonstrated that osthole is effective in inhibiting the proliferation of MDA-MB 435 cells, The mitochondrion-mediated apoptotic pathway was involved in apoptosis induced by osthole, as indicated by activation of caspase-9 and caspase-3 followed by PARP degradation. The mechanism underlying its effect on the induction of G1 phase arrest was due to the up-regulation of p53 and p21 and down-regulation of Cdk2 and cyclin D1 expression. Were observed taken together, these findings suggest that the anticancer efficacy of osthole is mediated via induction of cell cycle arrest and apoptosis in human breast cancer cells and osthole may be a potential chemotherapeutic agent against human breast cancer.

Osthole Induces Apoptosis, Suppresses Cell-Cycle Progression and Proliferation of Cancer Cells

Article

Full-text available

Nov 2014

Background: The aim of the present study was to determine the effects of osthole on cell proliferation and viability, cell-cycle progression and induction of apoptosis in human laryngeal cancer RK33 and human medulloblastoma TE671 cell lines. Materials and methods: Cell viability was measured by means of the MTT method and cell proliferation by the 5-bromo-2-deoxyuridine (BrdU) incorporation assay. Cell-cycle progression was determined by flow cytometry, and induction of apoptosis by release of oligonucleosomes to the cytosol. The gene expression was estimated by a quantitative polymerase chain reaction (qPCR) method. High-performance counter-current chromatography (HPCCC) was applied for isolation of osthole from fruits of Mutellina purpurea. Results: Osthole decreased proliferation and cell viability of cancer cells in a dose-dependent manner. The tested compound induced apoptosis, increased the cell numbers in G1 and decreased cell number in S/G2 phases of the cell cycle, differentially regulating CDKN1A and TP53 gene expression depending on cancer cell type. Conclusion: Osthole could be considered as a potential compound for cancer therapy and chemoprevention.

p53 Is a Key Regulator for Osthole-Triggered Cancer Pathogenesis

Article

Full-text available

Jun 2014
BMRI

Osthole has been reported to have antitumor activities via the induction of apoptosis and inhibition of cancer cell growth and metastasis. However, the detailed molecular mechanisms underlying the anticancer effects of osthole in human colon cancer remain unclear. In the present study, we have assessed osthole-induced cell death in two different human colon cancer cell lines, HCT116 and SW480. Our results also showed that osthole activated proapoptotic signaling pathways in human colon cancer cells. By using cell culture insert system, osthole reduced cell motility in both human colon cancer cell lines. This study also provides evidence supporting the potential of osthole in p53 activation. Expression of p53, an apoptotic protein, was remarkably upregulated in cells treated with osthole. Importantly, the levels of phosphorylation of p53 on Ser15 (p-p53) and acetylation of p53 on Lys(379) (acetyl-p53) were increased under osthole treatment. Our results also demonstrated that p53 was activated followed by generation of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK). Our study provides novel insights of p53-mediated responses under osthole treatment. Taken together, we concluded that osthole induces cancer cell death and inhibits migratory activity in a controlled manner and is a promising candidate for antitumor drug development.

Sphingolipids: Regulators of the Crosstalk between Apoptosis and Autophagy.

Article

Full-text available

Nov 2012

Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress. Although the two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators. The crosstalk between apoptosis and autophagy is complex, as autophagy can function to promote cell survival or cell death under various cellular conditions. The molecular mechanisms of crosstalk are beginning to be elucidated and have critical implications for the treatment of various diseases, such as cancer. Sphingolipids are a class of bioactive lipids that mediate many key cellular processes, including apoptosis and autophagy. By targeting several of the shared regulators, sphingolipid metabolites differentially regulate the induction of apoptosis and autophagy. Importantly, individual sphingolipid species appear to switch autophagy toward cell survival (e.g. sphingosine-1-phosphate) or cell death (e.g. ceramide, gangliosides). This review will assess the current understanding of sphingolipid-induced apoptosis and autophagy to address how sphingolipids mediate the switch between the cell survival and cell death. As sphingolipid metabolism is frequently dysregulated in cancer, sphingolipid-modulating agents, or sphingomimetics, have emerged as a novel chemotherapeutic strategy. Ultimately, a greater understanding of sphingolipid-mediated crosstalk between apoptosis and autophagy may be critical for enhancing the chemotherapeutic efficacy of these agents.

Growth Inhibition and Apoptosis Induced by Osthole, A Natural Coumarin, in Hepatocellular Carcinoma

Article

Full-text available

May 2012
PLOS ONE

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported. HCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array) assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment. Osthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of apoptosis-related genes.

Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway

Article

Full-text available

Mar 2011
J EXP CLIN CANC RES

To explore the effects of Osthole on the proliferation, cell cycle and apoptosis of human lung cancer A549 cells. Human lung cancer A549 cells were treated with Osthole at different concentrations. Cell proliferation was measured using the MTT assay. Cell cycle was evaluated using DNA flow cytometry analysis. Induction of apoptosis was determined by flow cytometry and fluorescent microscopy. The expressions of Cyclin B1, p-Cdc2, Bcl-2, Bax, t-Akt and p-Akt were evaluated by Western blotting. Osthole inhibited the growth of human lung cancer A549 cells by inducing G2/M arrest and apoptosis. Western blotting demonstrated that Osthole down-regulated the expressions of Cyclin B1, p-Cdc2 and Bcl-2 and up-regulated the expressions of Bax in A549 cells. Inhibition of PI3K/Akt signaling pathway was also observed after treating A549 cells with Osthole. Our findings suggest that Osthole may have a therapeutic application in the treatment of human lung cancer.

Immunomodulatory and Anti-Inflammatory Activity of Selected Osthole Derivatives

Article

Full-text available

Jun 2014
Z NATURFORSCH C

I From osthole [7-methoxy-8-(3-methyl-but-2-enyl)-chromen-2-one] (), obtained by selective extraction of Peucedanum ostruthium (L.) W. Koch roots, ostholic acid (II) was synthetized as a result of its oxidation with chromium trioxide. From ostholic acid, through its chloride, four amides were obtained: the morpholide 1, the p-chloro-benzylamide 2, the piperidine 3 and the N-methyl-piperazide 4. Except for 1, other compounds have not been described before. The amides 1 - 4 and their precursor osthole (I) were tested for their potential activities in selected immunological assays. The compounds showed moderate inhibitory activity in the humoral immune response to sheep erythrocytes in mice in vitro, and 4 was the most suppressive. The effects of 1 and 3 on concanavalin A- and pokeweed mitogen-induced mouse splenocyte proliferation were inhibitory and those of 4 stimulatory. The compounds were also tested for their activity on tumour necrosis factor α and interleukin 6 production, induced by lipopolysaccharide, in cultures of rat peritoneal cells and human peripheral blood mononuclear cells. Compounds 1, 3 and 4 inhibited tumour necrosis factor α (rat cells), whereas compound 2 stimulated the production of both cytokines. Compounds 1, 2 and 3 were also strongly inhibitory on tumour necrosis factor α production in human blood cells (73, 78 and 80% inhibition at 10 μg/ml, respectively). On the other hand, 2 and 4 stimulated the interleukin 6 production (2- to 3-fold stimulation). In addition, 2 and 4 suppressed the carrageenan-induced inflammation in mice (56.5% and 68.3% inhibition, respectively). In summary, the compounds predominantly displayed suppressive and anti inflammatory activities in the investigated models

Inhibition of Concanavalin A-Induced Mice Hepatitis by Coumarin Derivatives

Article

Full-text available

Feb 2001

The effects of coumarin derivatives, osthole, imperatorin, Pd-Ia, Pd-II and Pd-III, on mice concanavalin A (Con A) (0.2 mg/mouse, i.v.)-induced hepatitis were studied. At the dose of 200 mg/kg (i.p.), these coumarins inhibited more than 90% of the Con A-induced elevation of plasma alanine aminotransferase activity, but glycyrrhizin (200 mg/kg, i.p.) caused only 45% inhibition. At the dose of 100 mg/kg (i.p.), osthole produced the strongest inhibition among these coumarins. The inhibitory activity of osthole is lost when its 7-methoxy group is replaced by a 7-hydroxy group to form osthenol. The present results showed that coumarin derivatives inhibited Con A-induced hepatitis, with osthole being the most inhibitory.

Apoptosis, autophagy, and more

Article

Full-text available

Jan 2005
INT J BIOCHEM CELL B

Cell death has been subdivided into the categories apoptosis (Type I), autophagic cell death (Type II), and necrosis (Type III). The boundary between Type I and II has never been completely clear and perhaps does not exist due to intrinsic factors among different cell types and the crosstalk among organelles within each type. Apoptosis can begin with autophagy, autophagy can end with apoptosis, and blockage of caspase activity can cause a cell to default to Type II cell death from Type I. Furthermore, autophagy is a normal physiological process active in both homeostasis (organelle turnover) and atrophy. "Autophagic cell death" may be interpreted as the process of autophagy that, unlike other situations, does not terminate before the cell collapses. Since switching among the alternative pathways to death is relatively common, interpretations based on knockouts or inhibitors, and therapies directed at controlling apoptosis must include these considerations.

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Article

Full-text available

Jul 2005
NATURE

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.

Antitumor effects of Osthol from Cnidium monnieri: An in vitro and in vivo study

Article

Full-text available

Mar 2007

Cnidium monnieri (L.) Cusson is a Chinese medicine which is used widely by traditional medicine doctors. Osthol is a major bio-activity compound of the herb. In this study, osthol was isolated from C. monnieri and its in vitro and in vivo antitumor effects studied. The results of the in vitro study showed: that osthol inhibited the growth of HeLa, in a time- and concentration-dependent manner, with IC(50) values of 77.96 and 64.94 microm for 24 and 48 h, respectively; that osthol had lower cytotoxic effects in primary cultured normal cervical fibroblasts; and that increased DNA fragmentation and activated PARP in HeLa after treatment with osthol which could induce apoptosis. The results of the in vivo model showed that the survival days of the P-388 D1 tumor-bearing CDF(1) mice were prolonged (ILS% = 37) after osthol (30 mg/kg) was given once a day for 9 days. Based on these results, it is suggested that osthol could inhibit P-388 D1 cells in vivo and induce apoptosis in HeLa cells in vitro, and that osthol is good lead compound for developing antitumor drugs. However, C. formosanum Yabe of Taiwan's endemic plants contained little osthol, with no imperatorin, and its major components were different from that of C. monnieri. Therefore, it is suggested that C. formosanum also may possess economic worth.

Nimbolide induces apoptosis in human nasopharyngeal cancer cells

Article

Apr 2017
ENVIRON TOXICOL

Nasopharyngeal carcinoma (NPC), a tumor arising from epithelial cells that cover the surface and line the nasopharynx, is a rare malignancy worldwide but is prevalent in certain geographical areas, such as Southern Asia (Taiwan, Hong Kong, Singapore, Malaysia, and Southern China) and North Africa. Despite advances in diagnostic techniques and improvements in treatment modalities, the prognosis of NPC remains poor. Therefore, an effective chemotherapy regimen that enhances tumor sensitivity to chemotherapeutics is urgently required. Nimbolide, derived from Azadirachta indica, has a wide range of beneficial effects, including anti-inflammatory and anticancer properties. The present study evaluated the antitumor activity of nimbolide in NPC cells and its underlying mechanisms. Our results revealed that the treatment of HONE-1 cells with nimbolide potently inhibited cell viability. Moreover, nimbolide led to cell cycle arrest, which subsequently activated caspase-3, -8, and -9 and poly (ADP-ribose) polymerase to induce cell apoptosis. Moreover, nimbolide induced Bik, Bax, and t-Bid expression in HONE-1 cells. The results indicated that nimbolide induces apoptosis through the modulation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways. Nimbolide induces apoptosis in human NPC cells and is a potential chemopreventive agent against NPC proliferation.

Physcion, a naturally occurring anthraquinone derivative, induces apoptosis and autophagy in human nasopharyngeal carcinoma

Article

Oct 2016

Aim Physcion is a major bioactive ingredient in the traditional Chinese medicine Radix et Rhizoma Rhei, which has an anthraquinone chemical structure and exhibits a variety of pharmacological activities including laxative, hepatoprotective, anti-inflammatory, anti-microbial and anti-proliferative effects. In this study we investigated the effect of physcion on human nasopharyngeal carcinoma in vitro and in vivo, as well as the mechanisms underlying the anti-tumor action. Methods The nasopharyngeal carcinoma cell line CNE2 was treated with physcion, and cell viability was detected using MTT and colony formation assays. Flow cytometry was used to assess the cell cycle arrest, mitochondrial membrane potential loss, apoptosis, autophagy and intracellular ROS generation. Apoptotic cell death was also confirmed by a TUNEL assay. The expression of target or marker molecules was determined using Western blotting. The activity of caspase-3, 8, and 9 was detected with an ELISA kit. A xenograft murine model was used to evaluate the in vivo anti-tumor action of physcion, the mice were administered physcion (10, 20 mg·kg⁻¹·d⁻¹, ip) for 30 d. Results Treatment with physcion (5, 10, and 20 μmol/L) dose-dependently suppressed the cell viability and colony formation in CNE2 cells. Physcion (10 and 20 μmol/L) dose-dependently blocked cell cycle progression at G1 phase and induced both caspase-dependent apoptosis and autophagy in CNE2 cells. Furthermore, physcion treatment induced excessive ROS generation in CNE2 cells, and subsequently disrupted the miR-27a/ZBTB10 axis, resulting in repression of the transcription factor Sp1 that was involved in physcion-induced apoptosis and autophagy. Moreover, physcion-induced autophagy acted as a pro-apoptotic factor, and possibly contributed to physcion-induced apoptosis. In the xenograft murine model, administration of physcion dose-dependently suppressed the tumor growth without affecting the body weight. Furthermore, the anti-tumor effects of physcion were correlated with downregulation of Sp1 and suppression of miR-27a in the tumor tissues. Conclusion Physcion induces apoptosis and autophagy in human nasopharyngeal carcinoma by targeting Sp1, which was mediated by ROS/miR-27a/ZBTB10 signaling. The results suggest that physcion is a promising candidate for the treatment of human nasopharyngeal carcinoma.

Osthole, a Coumadin analog from Cnidium monnieri (L.) Cusson, stimulates corticosterone secretion by increasing steroidogenic enzyme expression in mouse Y1 adrenocortical tumor cells

Article

Oct 2015

Ethnopharmacological relevance: Osthole is an O-methylated Coumadin, which was isolated and purified from the seeds of Cnidium monnieri (L.) Cusson. Osthole is a commonly used traditional Chinese medicine to treat patients with Kidney-Yang deficiency patients, who exhibit clinical signs similar to those of glucocorticoid withdrawal. However, the mechanism of action of osthole is not fully understood. Objective: This study was designed to reveal the effects of osthole on corticosterone production in mouse Y1 cell. Materials and methods: Mouse Y1 adrenocortical cells were used to evaluate corticosterone production, which was quantified by enzyme-linked immunosorbent assay (ELISA) kits. Cell viability was tested using the MTT assay, and the mRNA and protein expression of genes encoding steroidogenic enzymes and transcription factors was monitored by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. Results: Osthole stimulated corticosterone secretion from mouse Y1 cells in a dose- and time-dependent manner, and osthole enhanced the effect of dibutyryl-cAMP (Bu2cAMP) on corticosterone production. Further, osthole also increased StAR and CYP11B1 mRNA expression in a dose-dependent manner and enhanced the expression of transcription factors such as HSD3B1, FDX1, POR and RXRα as well as immediate early genes such as NR4A1. Moreover, osthole significantly increased SCARB1(SRB1) mRNA and StAR protein expression in the presence or absence of Bu2cAMP; these proteins are an important for the transport of the corticosteroid precursor cholesterol transport into mitochondria. Conclusions: Our results show that the promotion of corticosterone biosynthesis and secretion is a novel effect of osthole, suggesting that this agent can be utilized for the prevention and treatment of Kidney-Yang deficiency syndrome.

Pterostilbene induce autophagy on human oral cancer cells through modulation of Akt and mitogen-activated protein kinase pathway

Article

Apr 2015

Extensive research supports the administration of herbal medicines or natural foods during cancer therapy. Pterostilbene, a naturally occurring phytoalexin, has various pharmacological activities, including antioxidant activity, cancer prevention activity, and cytotoxicity to many cancers. However, the effect of pterostilbene on the autophagy of tumor cells has not been clarified. In this study, the unique effects of pterostilbene on the autophagy of human oral cancer cells were investigated. The results of this study showed that pterostilbene effectively inhibited the growth of human oral cancer cells by inducing cell cycle arrest and apoptosis. In addition, the formation of acidic vesicular organelles and LC3-II production also demonstrated that pterostilbene induced autophagy. Administering 3-methylamphetamine (3-MA) and bafilomycin A1 (BafA1) exerted differing effects on the pterostilbene-induced death of human oral cancer cells. Pterostilbene-induced autophagy was triggered by activation of JNK1/2 and inhibition of Akt, ERK1/2, and p38. In conclusion, this study demonstrated that pterostilbene caused autophagy and apoptosis in human oral cancer cells, suggesting that pterostilbene could serve as a new and promising agent for treating human oral cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Osthole inhibits inflammatory cytokine release through PPARα/γ-mediated mechanisms in LPS-stimulated 3T3-L1 adipocytes

Article

Feb 2015
IMMUNOPHARM IMMUNOT

Context: Peroxisome proliferator-activated receptor (PPAR) α/γ may control inflammatory response by regulating the nuclear factor-kappa B (NF-κB). Osthole may be a dual agonist of PPARα/γ, but whether or not osthole may inhibit inflammatory cytokines in cultured 3T3-L1 adipocytes is unclear. Objective: We investigated the action of osthole and its potential mechanisms in lipopolysaccharide (LPS)-stimulated 3T3-L1 adipocytes. Materials and methods: The 3T3-L1 adipocytes stimulated with LPS were cultured and treated with different concentrations of osthole. The inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured supernatants were detected by the enzyme-linked immunosorbent assay (ELISA) method, and the protein expressions of PPARα/γ and NF-κB p65 in adipocytes were detected by the Western blot method, respectively. Results: Following treatment of adipocytes with osthole 0.1–1.6 μM, the TNF-α and IL-6 levels in cultured supernatants were decreased, and the NF-κB p65 protein expression in adipocytes was also decreased, while the PPARα/γ protein expressions were increased. After pretreatment of adipocytes with specific inhibitor(s) of PPARα and /or PPARγ, the inhibitory effects of osthole on TNF-α and IL-6 were decreased or almost cancelled, and the effects on NF-κB p65 protein expression also exhibited similar variations. Conclusion: Osthole could inhibit the TNF-α and IL-6 production in LPS-stimulated adipocytes, and its mechanism might be related to reduction of NF-κB expression via activation of PPARα/γ.

Effects of platycodin D in combination with different active ingredients of Chinese herbs on proliferation and invasion of 4T1 and MDA-MB-231 breast cancer cell lines

Article

Jan 2012

XH Han

Osthole, a Natural Coumarin Improves Cognitive Impairments and BBB Dysfunction After Transient Global Brain Ischemia in C57 BL/6J Mice: Involvement of Nrf2 Pathway

Article

Nov 2014
NEUROCHEM RES

Oxidative stress and blood–brain barrier (BBB) disruption play important roles in cerebral ischemic pathogenesis and may represent targets for treatment. Earlier studies have shown that osthole, a main active constituent isolated from Cnidium monnieri (L.) Cusson, could be considered as an attractive therapeutic agent in the treatment of ischemic stroke. However, the mechanism underlying the protective effect remains vague. In this study we aimed to investigate the effect of osthole on transient cerebral ischemia as well as its mechanism(s) in C57 BL/6 J mice. Mice were subjected to transient global cerebral ischemia induced by bilateral common carotid artery occlusion for 25 min. Behavioral test was performed at 4 days after ischemia, followed by assessment of neuronal loss in hippocampal CA1 region. Osthole significantly improved the cognitive ability and enhanced the survival of pyramidal neurons in the CA1 region of mice after lesion. Further studies showed that osthole attenuated the permeation of BBB, which may contribute to antioxidative effect by increasing the superoxide dismutase activity and decreasing the malondialdehyde level in model mice. Further studies revealed that osthole obviously up-regulated the protein levels of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 in HT22 cells. In conclusion, our findings indicated that osthole exerts neuroprotective effects against global cerebral ischemia injury by reducing oxidative stress injury and reserving the disruption of BBB, which may be attributed to elevating the protein levels of Nrf2 and HO-1.

Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-κB-mediated matrix metalloproteinase-9 expression

Article

Apr 2012
TOXICOL APPL PHARM

[Effects of platycodin D in combination with different active ingredients of Chinese herbs on proliferation and invasion of 4T1 and MDA-MB-231 breast cancer cell lines]

Article

Jan 2012

To investigate the effects of platycodin D in combination with different active ingredients of Chinese herbs under different therapeutic principles on proliferation and invasion of 4T1 and MDA-MB-231 breast cancer cell lines. The effective doses of platycodin D, Ophiopogon total saponins, curcumenol and osthole in inhibiting proliferation of breast cancer cell lines 4T1 and MDA-MB-231 were detected by methyl thiazolyl tetrazolium (MTT) assay, respectively. Optimized combinations of platycodin D with Ophiopogon total saponins, curcumenol, or osthole were determined by uniform design method. Effects of the optimized combinations of platycodin D with the three ingredients on proliferation and invasion of 4T1 and MDA-MB-231 cells were verified and evaluated by MTT assay and Transwell chamber test, respectively. Verifying study showed that the inhibitory effects of platycodin D in combination with curcumenol or osthole on proliferation of 4T1 and MDA-MB-231 cells were better than those of platycodin D in combination with Ophiopogon total saponins and each ingredient used alone (P<0.05 or P<0.01). The inhibitory effect of platycodin D in combination with Ophiopogon total saponins or osthole on invasion of 4T1 cells was significantly better than those of platycodin D in combination with curcumenol and each ingredient used alone (P<0.05 or P<0.01). Moreover, the inhibitory effect of platycodin D in combination with curcumenol or osthole on invasion of MDA-MB-231 cells was significantly better than that of platycodin D in combination with Ophiopogon total saponins (P<0.01). The optimized combinations of platycodin D with three different active ingredients of Chinese herbs under different therapeutic principles can significantly inhibit the proliferation and decrease the invasion of 4T1 and MDA-MB-231 cells. Different platycodin D combinations have different potency in suppressing breast cancer cell proliferation and invasion.

Inhibitory effects of osthole, psoralen and aconitine on invasive activities of breast cancer MDA-MB-231BO cell line and the mechanisms

Article

Oct 2011

To explore the inhibitory effects and to investigate the mechanisms of combined treatment of osthole, psoralen with aconitine on human breast cancer cell line MDA-MB-231BO. The best inhibitory concentration of osthole, psoralen combined with aconitine on MDA-MB-231BO cells was obtained by stepwise regression analysis after adopting a uniform experiment design. The invasive activities were observed by transwell assays, and expressions of transforming growth factor-β1 (TGF-β1), Smad2, Smad3, Smad4, Smad7, nuclear factor-κB (NF-κB) and receptor activator of NF-κB ligand (RANK) mRNAs were analyzed by real-time quantitative polymerase chain reaction. The optimal combination concentrations of osthol, psoralen and aconitine were 6.44, 8.89 and 9.44 μg/mL, respectively. Cell invasion was significantly inhibited after 24 hours of treatment using the combination drugs and zoledronic acid. TGF-β1, Smad2, Smad3, Smad4, Smad7, NF-κB and RANK mRNA expressions of the optimal combination group and zoledronic acid group were significantly reduced compared with the control group (P<0.01). Furthermore, TGF-β1, Smad2, Smad3, Smad4, Smad7, NF-κB and RANK mRNA expressions of the optimal combination group were significantly lower than those of the weak combination group (P<0.01). Combination treatment of osthole, psoralen with aconitine can inhibit cancer cell invasion, which is a result of alteration of the TGF-β/Smad signaling pathway and down-regulation of NF-κB and RANK expressions.

[Inhibitory acting mechanism of psoralen-osthole on bone metastasis of breast cancer--an expatiation viewing from OPG/RANKL/RANK system]

Article

May 2011

To find the optimal proportion of Composite Fructus Psoraleae and Fructus Cnidii (CFPC) for inhibiting the bone metastasis of breast cancer by way of exploring its acting mechanism viewing from OPG/RANKL/RANK system. The human bone metastasis of breast cancer model was established by injecting tumor cells of MDA-MB-231BO cell line into the left cardiac ventricle of nude mice. The modeled mice were randomly divided into seven groups: the blank group administered with normal saline by gastrogavage, the positive control group with zoledronic acid via peritoneal injection, and the 5 tested group with CFPC in different proportions of Fructus Psoraleae and Fructus Cnidii, i.e., (A, 4:0; B, 3:1; C, 1:1; D, 1:3, and E 0:4), given by gastric infusion. The treatment started from 1 week after modeling and lasted for six weeks. By the end of the experiment, the metastatic foci in bone were imaged by radionuclide tracing method and X-ray photograph, and separated for detecting gene and protein expressions of osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL), interleukin-8 (IL-8), parathyroid hormone-related protein (PTHrP), macrophage colony stimulating factor (MCSF) by Real-time PCR and Western blot respectively. Inhibition of bone metastasis gene was displayed to some extent in all the tested groups treated with CFPC, showing an increased level of OPG mRNA expression (It was 60.343 +/- 6.274 in the tested group C), and decreased mRNA expressions of IL-8, PTHrP, MCSF, RANKL (218.010 +/- 12.802, 232.399 +/- 14.354, 319.831 +/- 5.322, and 195.701 +/- 4. 862, respectively in the tested group C). The optimal effect was shown in the tested group C, showing significant difference to that in the blank group (P < 0.01). Meanwhile, the OPG in the bone metastatic foci could be up-regulated and protein expressions of RANKL/IL-8/PTHrP/MCSF down-regulated in all the tested groups. The optimal effect was shown in the tested group C, with significant difference from those of the normal saline group. CFPC could inhibit the bone metastasis of breast cancer through activating OPG/RANKL/RANK pathway. Among different proportions of Fructus Psoraleae and Fructus Cnidii, 1:1 was the best one.

Neuroprotective effect of osthole against acute ischemic stroke on middle cerebral ischemia occlusion in rats

Article

Dec 2010

Osthole, a natural coumarin derivative, has taken considerable attention because of its diverse pharmacological functions. It has been reported to be useful in the treatment of chronic cerebral hypoperfusion and neuronal damage. In the present study, we examined the neuroprotective effect of osthole and its potential mechanisms against acute ischemic stroke induced by middle cerebral artery occlusion (MCAO) in rats. The rats were pretreated with osthole 10, 20 and 40 mg/kg 30 min before MCAO. The neuroprotective effect of osthole against acute ischemic stroke was evaluated by neurological deficit score (NDS), dry-wet weight and 2,3,5-triphenyltetrazolium chloride (TTC) staining. The contents of malondialdehyde (MDA) and glutathione (GSH), activity of myeloperoxidase (MPO) and the level of interleukin (IL)-1β and IL-8 after 2h of MCAO in rats were detected to investigate its anti-oxidative action and anti-inflammatory property. Pretreatment with osthole significantly increased in GSH, and decreased the volume of infarction, NDS, edema, MDA, MPO, IL-1β and IL-8 compared with rats in the MCAO group at 24h after MCAO. The study suggests the neuroprotective effect of osthole in the MCAO model of rats. The anti-oxidative action and anti-inflammatory property of osthole may contribute to a beneficial effect against stroke.

Osthole Regulates Inflammatory Mediator Expression through Modulating NF-??B, Mitogen-Activated Protein Kinases, Protein Kinase C, and Reactive Oxygen Species

Article

Oct 2010
J AGR FOOD CHEM

Osthole, a coumarin compound, has been reported to exhibit various biological activities; however the cellular mechanism of its immune modulating activity has not yet been fully addressed. In this study we isolated osthole from the seeds of Cnidium monnieri and demonstrated that osthole inhibited TNF-α, NO and COX-2 expression in LPS-stimulated macrophages, without reducing the expression of IL-6. Furthermore, the phosphorylation of p38, JNK1/2, PKC-α and PKC-ε induced by LPS was inhibited by osthole; however, the phosphorylation of ERK1/2 and PKC-δ was not reduced by osthole. Osthole also inhibited NF-κB activation and ROS release in LPS-stimulated macrophages. Our current results indicated that osthole is the major anti-inflammatory ingredient of Cnidium monnieri seed ethanol extract.

Effects of Osthole on Migration and Invasion in Breast Cancer Cells

Article

Jul 2010
BIOSCI BIOTECH BIOCH

Osthole, a natural coumarin derivative, is extracted from the fruit of Cnidium monnieri Cusson. Breast cancer is one of the most commonly diagnosed cancers and the leading cause of death in women. Recent studies have shown that Osthole has anti-tumor activity. However, the effects of Osthole on the migration and invasion of cancer cells have not yet been reported. Here, we found that Osthole is effective in inhibiting the migration and invasion of breast cancer cells by wound healing and transwell assays. Luciferase and zymography assays revealed that Osthole effectively inhibits matrix metalloproteinase-2 promoter and enzyme activity, which might be one of the causes that lead to the inhibition of migration and invasion by Osthole. This is the first report on the inhibitory function of Osthole in migration and invasion in breast cancer cells. Our findings indicate a need for further evaluation of Osthole in breast cancer chemotherapy and chemoprevention.

Neuroprotective effect of osthole on MPP+-induced cytotoxicity in PC12 cells via inhibition of mitochondrial dysfunction and ROS production

Article

Oct 2010

The 1-methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it causes a severe Parkinson's disease-like syndrome accompanied by increased levels of intracellular reactive oxygen species (ROS) and apoptotic death. In the present study, we investigated the protective effects of osthole, a coumarin compound extracted from the plant-derived medicine Cnidium monnieri, on MPP(+)-induced cytotoxicity in cultured rat adrenal pheochromocytoma (PC12) cells. PC12 cells were treated with MPP(+) 2h after treated with different concentrations of osthole. 24h later, the cell viability, the release of lactate dehydrogenase, the activity of caspase-3 and cytochrome c, the expression ratio of Bax/Bcl-2 and the generation of intracellular ROS were detected. We found that pretreatment with osthole on PC12 cells significantly reduced the loss of cell viability, the release of lactate dehydrogenase, the activity of caspase-3 and cytochrome c, the increase in Bax/Bcl-2 ratio and the generation of intracellular ROS induced by MPP(+). Moreover, our HPLC analysis of cell extracts confirmed that extracellular osthole does penetrate the cell membrane. Thus osthole may function as an intracellular antioxidant to reduce oxidative stress induced by MPP(+). Therefore, the present study supports the notion that osthole may be a promising neuroprotective agent for the treatment of neurodegenerative disorders such as Parkinson's disease.

Osthole improves chronic cerebral hypoperfusion induced cognitive deficits and neuronal damage in hippocampus

Article

Mar 2010

This study is to investigate the effects of osthole on cognitive impairment and neuronal degeneration in hippocampus induced by chronic cerebral hypoperfusion in rats, as well as the potential mechanism. Permanent occlusion of bilateral common carotid arteries (2VO) induced severe cognitive deficits tested by the water maze task, along with oxidative stress and neuronal loss in hippocampus. Oral administration of osthole for 3 weeks markedly attenuated cognitive deficits and neuronal damage. Biochemical experiments revealed that osthole decreased the production of malondialdehyde (MDA) and significantly increased the activities of Glutathione Peroxidase (GPx) and Catalase. Western blot analyses indicated that osthole prevented the downregulation of bcl-2 expression and upregulation of bax expression, which resulted in decreasing bax/bcl-2 ratio in hippocampus of 2VO rats. Additionally, osthole effectively alleviated the activation of caspase-3 induced by permanent occlusion of bilateral common carotid arteries. The observed results in present study suggest that osthole exhibits therapeutic potential for vascular dementia, which is most likely related, at least in part, to its antioxidation and anti-apoptotic actions.

Antimetastatic effects of Terminalia catappa L. on oral cancer via a down-regulation of metastasis-associated proteases

Article

Apr 2010

The incidence and mortality of oral cancer in Taiwan have been increased during the last decade, which could be mainly resulted from the difficulty in treatment related to metastasis. As a potential and popular folk medicine, Terminalia catappa leaves have been proven to possess various biological benefits including anti-cancer activities. However, the detailed effects and molecular mechanisms of T. catappa leaves on the metastasis of oral cancer cells were still unclear. Thus, SCC-4 oral cancer cells were subjected to a treatment with ethanol extracts of T. catappa leaves (TCE) and then analyzed for the effect of TCE on the migration and invasion. Modified Boyden chamber assays revealed that TCE treatment significantly inhibited the cell migration/invasion capacities of SCC-4 cells. Furthermore, results of zymography and western blotting showed that activities and protein levels of MMP-2, MMP-9 and u-PA were all inhibited by TCE. Further studies indicated that TCE may inhibit phosphorylation of ERK1/2, JNK1/2 and Akt while the expression of nuclear protein NF-kappaB, c-Jun and c-Fos were inhibited as well. EMSA assay revealed that the DNA-binding activity with AP-1 and NF-kappaB was also decreased by TCE. In conclusion, TCE may serve as a powerful chemopreventive agent against oral cancer metastasis.

Antiproliferative effect in rat vascular smooth muscle cells by osthole isolated from Angelica pubescens

Article

Apr 1996
EUR J PHARMACOL

The antiproliferative effect of osthole on rat vascular smooth muscle cells was examined in this study. A number of mitogenic agents, e.g., foetal-calf serum (10%, v/v) and platelet-derived growth factor (20 ng/ml), and pharmacological agents, e.g., serotonin (10 microM), ionomycin (3 nM), phorbol 12,13-dibutyrate (20 nM) and phorbol myristate acetate (200 nM), were used to induce DNA synthesis in rat vascular smooth muscle cells; these effects were concentration dependently inhibited by osthole and the half-maximal inhibition (IC50) occurred at 13.6 +/- 1.8, 11.8 +/- 1.3, 7.9 +/- 0.9, 7.1 +/- 0.2, 7.8 +/- 0.2 and 8.6 +/- 0.4 microM, respectively. Osthole itself increased the cyclic AMP and cyclic GMP formations in a concentration-dependent manner; it synergistically increase cyclic AMP and cyclic GMP levels induced by forskolin and sodium nitroprusside, respectively. After 48 h deprivation of serum, cells were re-stimulated with serum and the cell cycle was observed by flow cytometry; treatment of cells with osthole (100 microM) caused a block of serum-inducible cell cycle progression at a point before the G1-S boundary. The addition of osthole (100 microM) at various times after serum addition to serum-deprived cells showed full inhibition of DNA synthesis even when added 6 h after serum. The cell cycle progression block was gradually lost as the delay from serum to osthole application was increased from 6 to 18 h. The effect of osthole on serum-stimulated [3H]thymidine incorporation into endothelial cells was examined and the IC50 value (158.7 +/- 2.7 microM, n = 6) was obtained; it exhibited greater potency (12-fold) for vascular smooth muscle cells as compared with endothelial cells as an antiproliferative agent. These results suggest that osthole is a selective antiproliferative agent in vascular smooth muscle cells. The antiproliferative effect occurs at the early G1 phase of the cell cycle and is due to the increase in cyclic AMP and cyclic GMP contents.

Chemical Aspects of Coumarin Compounds for the Prevention of Hepatocellular Carcinomas

Article

Feb 2005
Curr Med Chem Anti Canc Agents

The normalization of plasma alanine aminotransferase (ALT) has been proved to be a strategy for preventing the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infection. Glycyrrhizin, a plant medicine, normalizes plasma ALT and prevents HCC. However, glycyrrhizin is administered intravenously and thereby chemical which is effective on oral administration is required. Coumarin compounds are active components of herbs used for the treatment of various diseases. The ability of coumarin compounds to lower plasma ALT were examined using mice concanavalin A-induced hepatitis and mice anti-Fas antibody-induced hepatitis. Furanocoumarins pd-Ia, pd-II and pd-III lower plasma ALT, but they are large molecules that are hardly absorbed on oral administration. Furocoumarin effectively lowers plasma ALT, but the safety range between the effective and toxic dosages is narrow. In contrast, osthole, a simple coumarin, causes strong reduction of plasma ALT and also inhibits caspase-3 activation. Furthermore, this chemical is quite safe upon large dose administration. In the structure of osthole, the methoxy group at position-7 and the 3-methyl-2-butenyl group at position-8 were elucidated to be essential for the beneficial effect of this chemical. We conclude that osthole will become a leading chemical for synthesizing a compound which prevents HCC on oral administration.

Specific alteration of the Bax/Bcl2 ratio and cytochrome c without execution of apoptosis in the hippocampus of aged baboons

Article

Feb 2005

During ageing, there may be an age-associated loss of particular nerve cells in specific brain areas. Recent studies highlight the role of apoptosis in the normal ageing of the brain, heart, and skeletal muscle. Particular attention is paid to the role of cytochrome c release from mitochondria and alterations in the pro- and anti-apoptotic proteins, Bax and Bcl-2, respectively. The aim of this study was to investigate the potential occurrence of apoptosis in the hippocampus of aged baboons. we have used the baboon as a potential non-human primate model for age-related pathology which afflicts the human brain. The TUNEL staining method was used to characterise the apoptotic cell death. For immunocytochemistry, antibodies directed against activated caspase-3, cytochrome c, Bcl-2 and Bax proteins were used. Our results show that in hippocampi of aged baboons the immunoreactivities of the antiapoptotic agent Bcl-2 was not prominently changed, of the proapoptotic agent Bax was upregulated, of the cytochrome c was redistributed, and that caspase-3 was not activated. The TUNEL-staining method revealed no apoptotic cell death in hippocampi of aged baboons. This demonstrates that a specific alteration of the Bax/Bcl2 ratio occurs in the ageing baboon hippocampus which may directly influence the release of cytochrome c even without commitment to apoptosis.

Coumarins from Cnidium monnieri and their Antiosteoporotic Activity

Article

Feb 2007

Bioactivity-guided fractionation has led to the successful isolation of antiosteoporotic components, i. e., osthole, imperatorin and bergapten from an ethanolic extract of the fruits of Cnidium monnieri (L.) Cusson. Among them, osthole was determined as the major compound possessing antiosteoporotic activity. Further study showed that osthole not only promoted the proliferation and activity of alkaline phosphatase of osteoblasts in neonatal calvaria cultures, but also inhibited the bone resorption by decreasing the formation, differentiation and TRAP activity of osteoclasts derived from rat marrow cells.

Osthole induces human nasopharyngeal cancer cells apoptosis through Fas-Fas ligand and mitochondrial pathway

Abstract

No full-text available

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