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(A) Wound healing assay, panc-1 cells grown at 80% confluency. The monolayers were incised with a pipette tip in the central area of the culture. TGF-β1 and Nar was added as indicated times. Photographs were taken using phase-contrast microscopy (magnification at ×100) immediately after the incision and after 36 h and 72 h of treatment. (B and C) Transwell invasion assay (B for aspc-1 cells and C for panc-1cells). In Matrigel-coated cell culture insert, cells were treated as described in Materials and methods. The cells that had invaded to the lower surface of the filter were stained with crystal violet and photographed. (D) Transwell migration assays. In non-Matrigel-coated cell culture insert, to quantify migration, the stained cells were lysed in DMSO and their absorbance was measured. (E) Cell was treated with 5 ng/ml TGF-β1 for 30 h, the phenomenon of EMT was observed by cell morphological changes. These experiments were done triplicate. *p<0.05; **p<0.01; ***p<0.005.
Source publication
Epithelial to mesenchymal transition (EMT) promotes cellular motility, invasiveness and metastasis during embryonic development and tumorigenesis. Transforming growth factor-β (TGF-β) signaling pathway is a key regulator of EMT. A lot of evidences suggest that this process is Smad3-dependent. Herein we showed that exposure of aspc-1 and panc-1 panc...
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The effects of berberine on the metastatic potential of lung cancer cells and its underlying mechanisms have not been fully elucidated. Since epithelial-to-mesenchymal transition is a cellular process associated with cancer invasion and metastasis, we attempted to investigate the potential use of berberine as an inhibitor of TGF-beta1-induced epith...
Citations
... Importantly, Naringin intervened by inhibiting the TGF-b1/Smad3 signaling pathway, effectively curbing both the mRNA and protein expression of EMT markers in these pancreatic cancer cells [141]. Consequently, naringin not only suppressed their migration and invasion capabilities but also reversed their acquired resistance to gemcitabine [142]. In TNF-ainduced VSMC, treatment with the aglycone naringenin yielded comparable outcomes to naringin [143]. ...
Cancer stands as a significant contributor to global mortality rates, primarily driven by its progression and widespread dissemination. Despite notable strides in cancer therapy, the efficacy of current treatment strategies is compromised due to their inherent toxicity and the emergence of chemoresistance. Consequently, there is a critical need to evaluate alternative therapeutic approaches, with natural compounds emerging as promising candidates, showcasing demonstrated anticancer capabilities in various research models. This review manuscript presents a comprehensive examination of the regulatory mechanisms governing the expression of matrix metalloproteinases (MMPs) and delves into the potential therapeutic role of flavonoids as agents exhibiting specific anticancer activity against MMPs. The primary aim of this study is to elucidate the diverse functions associated with MMP production in cancer and to investigate the potential of flavonoids in modulating MMP expression to inhibit metastasis.
... Similar results were found with ursolic acid (25 μM) treatment against the migration capabilities of the human gastric carcinoma cells BGC823 associated with a negative modulation of the NF-κB pathway and vimentin, Snail, and Twist gene expression 167 . Concerning polyphenols, naringenin (50 µM) prevents TGF-β induction of EMT in the pancreatic carcinoma cells panc-1 by inhibiting the Smad3 pathway, impairing migration, invasion, and the mesenchymal phenotype as noted by the repression of vimentin and N-cadherin 168 . Interestingly, apigenin (20 μM) reverses EMT in the human hepatocarcinoma cells Bel-7402 as indicated by changes in cell morphology and reexpression of E-cadherin and claudin-3 linked to repression of the NF-κB and Snail axis 169 . ...
There is an urgent need to develop new therapies for cancer treatment due to high rates of resistance and tumor relapse. Moreover, chemotherapy and radiation weaken the immune system and leave patients susceptible to sudden death from infections and organ failure since antineoplastic drugs lack specificity. Hence, scientists worldwide continue the search for natural alternatives with anticancer activities and fewer side effects. In this regard, traditional medicine offers strategies for preventing and treating numerous diseases and nowadays scientific studies worldwide highlight some of the mechanisms underlying their potential as an effective alternative for the management of cancer. In Mexico, Mayan healers have been prescribed mainly medicinal plants for more than 2,000 years. Furthermore, their ethnomedical knowledge has led to drug discovery or the development of herbal remedies. Medicinal plants from the genus of Cissus remain an important element of all indigenous medical systems in Mexico including the Mayan tribes in Yucatan, particularly for the management of gastrointestinal illnesses, sores, cutaneous diseases, and tumors. In this review, we present the reported bioactivities against cancer cells of the extract and compounds from the species of Cissus with a particular focus on recent studies on the phytochemistry of C. trifoliata which is widely distributed in Mexican territory and used for tumor management in traditional medicine.
... Additionally, naringin has antioxidant, anti-inflammatory, and DNA-protecting properties (Gelen et al. 2018). As mentioned also, naringenin can alleviate inflammation and cell death (Jayaraman et al. 2012;Lou et al. 2012;Wali et al. 2020). ...
... Additionally, naringin has antioxidant, anti-inflammatory, and DNA-protecting properties (Gelen et al. 2018). As mentioned also, naringenin can alleviate inflammation and cell death (Jayaraman et al. 2012;Lou et al. 2012;Wali et al. 2020). ...
This research aimed to evaluate the preventing effects of naringin, naringenin, and their combination on liver injury induced by Taxol (paclitaxel) in Wistar rats. Male Wistar rats received 2 mg/kg Taxol intraperitoneal injections twice weekly on the second and fifth days of each week for 6 weeks. During the same period as Taxol administration, rats were given naringin, naringenin, or a combination of the two (10 mg/kg b.wt) every other day. Treatment with naringin and/or naringenin reduced the abnormally high serum levels of total bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma-glutamyl transferase in Taxol-treated rats. It also significantly increased the level of serum albumin, indicating an improvement in the liver. The perturbed histological liver changes were markedly improved due to the naringin and/or naringenin treatment in Taxol-administered rats. Additionally, the treatments reduced high hepatic lipid peroxidation and increased liver glutathione content as well as the activities of superoxide dismutase and glutathione peroxidase. Furthermore, the treatments reduced the levels of alpha-fetoprotein and caspase-3, a pro-apoptotic mediator. The naringin and naringenin mixture appeared more effective in improving organ function and structural integrity. In conclusion, naringin and naringenin are suggested to employ their hepatoprotective benefits via boosting the body’s antioxidant defense system, reducing inflammation, and suppressing apoptosis.
Graphical Abstract
... In glioblastoma cells, naringenin inhibited invasion and metastasis through multiple mechanisms, including EMT modulation, as evidenced by the alteration of EMT biomarkers [79]. In pancreatic cancer cells, naringenin downregulated EMT markers by inhibiting the TGF-β/Smad3 pathway; consequently, invasiveness and metastasis of cells were decreased [80]. ...
A biological process called epithelial-mesenchymal transition (EMT) allows epithelial cells to change into mesenchymal cells and acquire some cancer stem cell properties. EMT contributes significantly to the metastasis, invasion, and development of treatment resistance in cancer cells. Current research has demonstrated that phytochemicals are emerging as a potential source of safe and efficient anti-cancer medications. Phytochemicals could disrupt signaling pathways related to malignant cell metastasis and drug resistance by suppressing or reversing the EMT process. In this review, we briefly describe the pathophysiological properties and the molecular mechanisms of EMT in the progression of cancers, then summarize phytochemicals with diverse structures that could block the EMT process in different types of cancer. Hopefully, these will provide some guidance for future research on phytochemicals targeting EMT.
... Preciously, we have demonstrated that naringenin inhibits TGF-β1/Smad3 signaling pathway via the decrease of smad3 expression and can directly block receptor interaction [35,36], leading to the reduction of Tregs production. Naringenin (YPS345) has been proved to effectively relieve radiation induced pulmonary inflammation and fibrosis [37], which is currently in an ongoing phase II clinical trial in China (NO. ...
Background
Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-β1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-β1 is secreted in an extracellular vesicles-associated form (TGF-β1EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-β1EV will pave a way for overcoming the radiotherapy resistance in cancer treatment.
Methods
The superoxide-Zinc-PKC-ζ-TGF-β1EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student’s t test or two-way ANOVA with correction was used for comparisons of groups.
Results
The radiotherapy resulted in an increased expression of the intratumoral TGF-β1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-β1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-β1EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-β1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-β1EV pathway.
Conclusions
The superoxide-zinc-PKC-ζ-TGF-β1EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-β1EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers.
Trial registration: The using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).
... The result showed that naringenin has the highest binding energy of À45.9 Kcal/mol, suggesting stronger binding to p63 than the other ligands. It has been reported that naringenin suppresses epithelial-mesenchymal transition (EMT) markers by blocking the TGF-b1/Smad3 signal process in the pancreatic cancer cell at the mRNA and protein levels (Lou et al., 2012). During embryonic development, EMT is known to play a vital role in cellular motility, invasiveness, and metastasis (Rauf et al., 2022). ...
Pancreatic ductal adenocarcinoma is an aggressive malignancy usually detectable at the advanced stage, with a 5-year survival rate of less than 8%. It has been reported that a gene called tumor-protein 63 (TP63) is expressed in an aggressive form of pancreatic cancer with a squamous signature. Thus, inhibiting the activity of p63 can be a means of treating and managing PDA. Different studies have shown that plant constituents are rich and can be a promising source for discovering drug candidates. The extract from mistletoe (Viscum album) is known to contain anticancer compounds; however, the specific molecular mechanism of the bioactive compounds is unknown. This study examines the pancreatic cancer therapeutic potential of the bioactive compounds in the flavonoid and phenolic acid constituents of mistletoe by adopting structural bioinformatics and advanced theoretical chemistry techniques via molecular docking, molecular dynamics simulation, molecular mechanics/generalized Born surface area (MM/GBSA) calculations, pharmacokinetic analysis, and density functional theory analysis. The six best compounds from the flavonoid constituent with the highest binding affinity ranging from −6.8 kcal/mol to −6.7 kcal/mol were selected with the control gemcitabine (−5.5 kcal/mol) for further computational analysis after molecular docking. Furthermore, MM/GBSA calculation showed the highest binding energy for the selected docked compounds, which validates their inhibitory potential. Hence, the molecular dynamics simulation, post-simulation analysis, pharmacokinetics model, and DFT results showed that mistletoe compounds are reliable due to their stable interaction with the target protein and drug-likeness properties.
Communicated by Ramaswamy H. Sarma
... Naringenin, a flavonoid abundantly present in citrus species, inhibits the transforming growth factor beta (TGF-β) induced epithelial-mesenchymal transition (EMT). It reduces EMT and decreases invasiveness and metastasis in PC cells [14]. Resveratrol is present in nuts, berries, and grapes, especially in the skin and it has been shown to exert anticancer activities [15]. ...
Background:
Pancreatic cancer metastasis is characterized by a higher incidence of morbidity and mortality. The present study attempts to identify phytocomponents with the potential to inhibit the secretion of MMP-2 by pancreatic cancer cells and ascertain the efficacy of individual components.
Methods:
Overall survival analysis carried out revealed reduced survival of patients with high MMP-2 expression. Data analysis from TCGA revealed increased MMP-2 expression in pancreatic cancer patients compared to adjacent normal tissues. The expression of MMP-2 was reported at different stages of pancreatic cancer (Stage I-IV). To understand the relevance of phytocomponents in binding to the catalytic site of MMP-2, molecular docking studies were performed to find the effectiveness based on Glide score/energy. To substantiate the in-silico analysis, the eight components were also tested in vitro for reducing the survival in PANC-1 cells at three different time points (24, 48, and 72 hours). Finally, zymography analysis was performed using the eight components in the PANC-1 conditioned media of treated cells to ascertain the enzymatic activity of MMP-2.
Results:
The obtained results suggest plumbagin, emodin, and EGCG exert potential inhibition in PANC-1 cells, among other phytocomponents tested. Therefore, as assessed using computational studies, the binding ability of plumbagin, emodin, and EGCG can be interpreted as inhibiting effects on MMP-2 activities.
Conclusion:
These compounds could find potential application in preventing the progression, sustenance, and metastasis of pancreatic cancer and need to be explored further using a pre-clinical model system in order to validate the efficacy, bioavailability, and safety.
... Preciously, we have demonstrated that naringenin inhibited TGF-β1/Smad3 signaling pathway via the decrease of smad3 expression and directly block receptor interaction [40,41], leading to reduction of Tregs production, which let it be a promising candidate for the development of potential anti-TGF-β1 agents in the clinic. Naringenin (YPS345) has been proved to effectively relieve radiation induced ...
Background: Radiotherapy is widely applied to breast cancer treatment, while the resistance to radiotherapy is inevitable. TGF-β1 has been considered to be an endogenous factor for RT resistance. As a large portion of TGF-β1 is secreted associating with the extracellular vesicles (TGF-β1EV), to understand the regulation mechanisms and the immunosuppressive function of TGF-β1EV in the radiated tumors will pay a way for overcoming radiotherapy resistance.
Methods: Based on TCGA database of 958 samples, the intratumoral TGF-β1 expression and the Tregs production were compared between patients received and unreceived radiotherapy. The superoxide-Zinc-PKC-ζ-TGF-β1EV pathway in breast cancer cells were identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth was determined using observation of the animals and tumor growth measurement. Student’s t test or type II ANOVA with correction was used for comparisons of groups.
Results: The radiotherapy brought the increased intratumoral TGF-β1 expression and the Tregs production in the breast cancer tissues, and patients with higher TGF-β1 expression are associated with a poor survival. The increased intratumoral TGF-β mainly exists in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced the more secretion of the TGF-β1EV and the higher percentage of Tregs by promoting protein kinase C zeta (PKC-ζ) expression and phosphorylation. Importantly, we found that naringenin rather than 1D11 significantly improve radiotherapy efficacy with low side effects. The underlying mechanism of naringenin is via downregulating radiation activated the superoxide-Zinc-PKC-ζ-TGF-β1EV pathway, which is distinct from TGF-β1 neutralizing antibody 1D11.
Conclusions: The superoxide-zinc-PKC-ζ-TGF-β1EV release pathway was elucidated to induce the accumulation of Tregs resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-β1EV function could represent a novel strategy to overcome radioresistance in breast cancer treatment or other cancers.
Trial registration: Using of tissues from patients with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).
... Naringenin (20, 40 and 80 µM) downregulated MMP-2 and MMP-9 and subsequently inhibited migration in gastric cancer SGC-7901 cells [43]. Naringenin (50 µM and 100 µM) blocked TGF-1/SMAD3 downstream signals, reduced the expression of mesenchymal markers and attenuated MMP-2 and MMP-9 activities, consequently suppressing migration and invasion in pancreatic cancer panc-1 and aspc-1 cells [99]. Naringenin (300 µM over a period of 24 h) decreased AKT and MMP-2 activities and inhibited migration of TSGH-8301 bladder cancer cells [100] and proliferation of A549 lung cancer cells [40]. ...
Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health and has been practiced since ancient times. Numerous studies have reported these substances’ antioxidant and antiandrogenic properties, as well as their ability to protect from inflammation and cancer, in various in vitro and in vivo experimental models in animals and humans. Naringin and naringenin can suppress cancer development in various body parts, alleviating the conditions of cancer patients by acting as effective alternative supplementary remedies. Their anticancer activities are pleiotropic, and they can modulate different cellular signaling pathways, suppress cytokine and growth factor production and arrest the cell cycle. In this narrative review, we discuss the effects of naringin and naringenin on inflammation, apoptosis, proliferation, angiogenesis, metastasis and invasion processes and their potential to become innovative and safe anticancer drugs.
