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Both long-term anti-estrogen therapy and estrogen receptor-negative breast cancer contribute to drug resistance, causing poor prognosis in breast cancer patients. Breast cancer resistance protein (BCRP) plays an important role in multidrug resistance. Here, we show that cryptotanshinone (CPT), an anti-estrogen compound, inhibited the oligomer forma...
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Citations
... However, CPT can not bind to FKBP12, but activate AMPK-TSC2 axis to inhibit mTORC1 signaling [16]. Furthermore, we also found that CPT inhibited mTOR dependent on estrogen receptor ɑ in breast cancer [29], and reversed multidrug resistance of breast cancer by inhibiting BCRP oligomer formation [30]. Here, CPT reduced the content of key glycolytic metabolites, inhibited the kinase of PFK and Fig. 8 The molecular mechanism diagram of CPT inhibiting melanoma cell proliferation the protein expression of PFKFB3 in melanoma cells, suggesting that CPT can interrupt the glucose metabolism of melanoma cells. ...
Background
Cutaneous melanoma is a kind of skin malignancy with low morbidity but high mortality. Cryptotanshinone (CPT), an important component of salvia miltiorrhiza has potent anti-tumor activity and also indicates therapeutic effect on dermatosis. So we thought that CPT maybe a potential agent for therapy of cutaneous melanoma.
Methods
B16F10 and A375 melanoma cells were used for in vitro assay. Tumor graft models were made in C57BL/6N and BALB/c nude mice for in vivo assay. Seahorse XF Glycolysis Stress Test Kit was used to detect extracellular acidification rate and oxygen consumption rate. Si-RNAs were used for knocking down adenosine monophosphate-activated protein kinase (AMPK) expression in melanoma cells.
Results
CPT could inhibit the proliferation of melanoma cells. Meanwhile, CPT changed the glucose metabolism and inhibited phosphofructokinase (PFK)-mediated glycolysis in melanoma cells to a certain extent. Importantly, CPT activated AMPK and inhibited the expression of hypoxia inducible factor 1α (HIF-1α). Both AMPK inhibitor and silencing AMPK could partially reverse CPT’s effect on cell proliferation, cell apoptosis and glycolysis. Finally, in vivo experimental data demonstrated that CPT blocked the growth of melanoma, in which was dependent on the glycolysis-mediated cell proliferation.
Conclusions
CPT activated AMPK and then inhibited PFK-mediated aerobic glycolysis leading to inhibition of growth of cutaneous melanoma. CPT should be a promising anti-melanoma agent for clinical melanoma therapy.
... From the tanshinone biogenesis pathway, it is clear that hypotanshinone diene is the first product in the formation of the tanshinone skeleton, and through a series of biosynthetic pathways, active ingredients such as tanshinone IIA and CPT are finally formed in reactions catalyzed by the cytochrome P450 enzyme oxidases, decarboxylase, dehydrogenase, and reductase. 5 Although there have been some reports on the anticancer benefits of CPT on several malignancies, such as lung, 6 colorectal, 7 breast, 8 and bladder 9 cancer, and chronic myeloid leukemia, 10 it is unclear exactly how CPT exerts its anticancer activity. ...
Cryptotanshinone is a quinone diterpene extracted from the traditional Chinese medicine Salvia miltiorrhiza root that shows obvious anticancer activity. The aim of this study was to investigate the mechanism of action of cryptotanshinone as an antigastric cancer agent, as well as a chemotherapy potentiator. A gastric cancer model was established by tumor transplantation, and mice were treated with either 5-fluorouracil or cryptotanshinone, or both drugs. The tumor mass was recorded, and the tumor suppression rate was calculated. Pathological changes were observed by hematoxylin and eosin staining, gene transcription was detected by quantitative polymerase chain reaction, and protein expression by Western blotting. The results showed that cryptotanshinone could reduce the tumor mass, increase the tumor suppression rate, and enhance the chemotherapeutic effect of 5-fluorouracil by a mechanism related to inhibition of the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway.
... Thus, Ni et al. (2021) stated that BCRP might have a vital role in regulating the CPT transportation across the breast cancer cells membrane. They found that although CPT could not affect the intracellular protein and mRNA levels of BCRP/ABCG2, but inhibited the efflux function of BCRP in MCF-7 cells by reducing the BCRP expression on the cell membrane, which was ERαdependent ( Figure 2). ...
... To find whether CPT was synergistic with BCRP-mediated efflux of anticancer drugs or not, they investigated the effect of CPT along with two of the most common BCRP drugs, MX and TOPO, compared with treatment with MX or TOPO alone. The findings showed that CPT increased the efficacy of chemotherapy drugs that can be effluxed by BCRP from tumor cells, reversing MDR (Ni et al., 2021). ...
Breast cancer has recently been known as the first lethal malignancy in women worldwide. Despite the existing treatments that have improved the patients’ prognosis, some types of breast cancer are serious challenges to treat. Therefore, efforts are underway to provide more efficient therapy. Cryptotanshinone (CPT) is a liposoluble diterpenoid derivation of a traditional Chinese herbal medicine called Salvia miltiorrhiza Bunge. It has been considered in the past decades due to its vast therapeutic properties, including anti-tumor, anti-inflammatory, and anti-fibrosis. Recently, studies have found that CPT showed a significant anti-breast cancer effect in vivo and in vitro through different physiological and immunological mechanisms. This study summarized the latest research findings on the antitumor effect of CPT in breast cancer. Further, the main molecular mechanisms based on breast cancer types and combination with other drugs were reviewed to provide essential evidence for future longitudinal research and its clinical application in breast cancer treatment.
... Dihydroisotanshinone I (25) inhibited the proliferation of BC cells via inducing their ferroptosis and apoptosis (Lin et al., 2019). Cryptotanshinone (26) inhibited migration through inactivating PKM2/β-Catenin signaling, and mediated drug resistance via reducing the oligomer formation of breast cancer resistance protein on the cell membrane, and thus blocking its efflux function Ni et al., 2021). Tanshinone I (27) inhibited the proliferation of MDA-MB-231 cells via activating the AMPactivated protein kinase mediating autophagic signaling (Zheng et al., 2020). ...
Breast cancer (BC) is a kind of malignant cancer in women, and it has become the most diagnosed cancer worldwide since 2020. Histone methylation is a common biological epigenetic modification mediating varieties of physiological and pathological processes. Lysine-specific demethylase 1 (LSD1), a first identified histone demethylase, mediates the removal of methyl groups from histones H3K4me1/2 and H3K9me1/2 and plays a crucial role in varieties of cancer progression. It is also specifically amplified in breast cancer and contributes to BC tumorigenesis and drug resistance via both demethylase and non-demethylase manners. This review will provide insight into the overview structure of LSD1, summarize its action mechanisms in BC, describe the therapeutic potential of LSD1 inhibitors in BC, and prospect the current opportunities and challenges of targeting LSD1 for BC therapy.
... More recently, Ni et al. [67] demonstrated that 13 inhibited the oligomer formation of Breast cancer resistance protein (BCRP) on the cell membrane, thus blocking its efflux function. This activity is strictly dependent on the expression level of estrogen receptor a (ERa) in ERa-positive breast cancer cells. ...
Extensive research over the past decades has identified numerous phytochemicals that could represent an important source of anti-cancer compounds. There is an immediate need for less toxic and more effective preventive and therapeutic strategies for the treatment of cancer. Natural compounds are considered suitable candidates for the development of new anti-cancer drugs due to their pleiotropic actions on target events with multiple manners. This comprehensive review highlighted the most relevant findings achieved in the screening of phytochemicals for anticancer drug development, particularly focused on a promising class of phytochemicals such as diterpenes with abietane, clerodane, and labdane skeleton. The chemical structure of these compounds, their main natural sources, and mechanisms of action were critically discussed.
... Moreover, Xiaoman Liu et al. (Liu et al., 2016) demonstrated that CPT inhibited migration and proliferation of ER-negative Bcap37 cells in breast cancer, and they also observed some post-treatment features of apoptotic morphological changes in Bcap37 cells, for instance, fragmentation of DNA and nuclear condensation. Another suggested mechanism is the effects of CPT on silencing BCRP (breast cancer resistance protein) expression in breast cells, reported by Wenting ni et al. (Ni et al., 2020). BCRP plays the main role in causing resistance in malignant cells of breast (Nakanishi and Ross, 2012). ...
Cancer is among the most life-threatening diseases worldwide. Along with conventional therapies like chemotherapy, surgery, and radiotherapy, alternative treatment approaches such as traditional Chinese medicine have attracted considerable public and scientific interest that could be beneficial for patients diagnosed with cancer. Salvia miltiorrhiza Bunge is greatly beloved for its roots and is extensively applied for various disease therapies, including cancers in traditional Chinese medicine. In this review, we intend to summarize the anti-cancer properties of Cryptotanshinone (CPT), an extract of Danshen (the root of Salvia miltiorrhiza Bunge), on different types of cancer.
... In addition, molecular modeling studies were carried out between P-gp and terpenoids (Cardoso et al., 2021;Hasan et al., 2021;Isca et al., 2020;Laiolo et al., 2021;Rybalkina et al., 2021;Shaker et al., 2020;Yang et al., 2021), flavonoids (Marques et al., 2021), and other alkaloids Gu and Guo, 2013;Kazemi et al., 2021;Palko--Łabuz et al., 2021;Sami Bawazeer et al., 2021;Yalcin, 2020;Zeng et al., 2021). In the literature, molecular modeling studies have been found between other MDR efflux transporters, ABCG2 (Fan et al., 2019;Le et al., 2021;Ni et al., 2021;Wu et al., 2021b), and ABCC1 Gonçalves et al., 2020), ABCC4 (Berthier et al., 2021), and natural products. While the studies carried out with small synthetic molecules were examined, drug development studies were found for ABC (J. ...
Cancer remains a leading cause of morbidity and mortality worldwide. Hence, the increase in cancer cases observed in the elderly population, as well as in children and adolescents, makes human malignancies a prime target for anticancer drug development. Although highly effective chemotherapeutic agents are continuously developed and approved for clinical treatment, the major impediment towards curative cancer therapy remains multidrug resistance (MDR). In recent years, intensive studies have been carried out on the identification of new therapeutic molecules to reverse MDR efflux transporters of the ATP-binding cassette (ABC) superfamily. Although a great deal of progress has been made in the development of specific inhibitors for certain MDR efflux pumps in experimental studies, advanced computational studies can accelerate this drug development process. In the literature, there are many experimental studies on the impact of natural products and synthetic small molecules on the reversal of cancer MDR. Molecular modelling methods provide an opportunity to explain the activity of these molecules on the ABC-transporter family with non-covalent interactions as well as it is possible to carry out studies for the discovery of new anticancer drugs specific to MDR with these methods. The coordinate file of the 3-dimensional (3D) structure of the target protein is indispensable for molecular modelling studies. In some cases where a 3D structure cannot be obtained by experimental methods, the homology modelling method can be applied to obtain the file containing the target protein's information including atomic coordinates, secondary structure assignments, and atomic connectivity. Homology modelling studies are of great importance for efflux transporter proteins that still lack 3D structures due to crystallization problems with multiple hydrophobic transmembrane domains. Quantum mechanics, molecular docking and molecular dynamics simulation applications are the most frequently used molecular modelling methods in the literature to investigate non-covalent interactions between the drug-ABC transporter superfamily. The quantitative structure-activity relationship (QSAR) model provides a relationship between the chemical properties of a compound and its biological activity. Determining the pharmacophore region for a new drug molecule by superpositioning a series of molecules according to their physicochemical properties using QSAR models is another method in which molecular modelling is used in computational drug development studies with ABC transporter proteins. There are also in silico absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) studies conducted to make a prediction about the pharmacokinetic properties, and drug-likeness of new molecules. Drug repurposing studies, which have become a trending topic in recent years, involve identifying possible new targets for an already approved drug molecule. There are few studies in the literature in which drug repurposing performed by molecular modelling methods has been applied on ABC transporter proteins.
The aim of the current paper is to create a complete review of drug development studies including aforementioned molecular modelling methods carried out between the years 2019-2021. Furthermore, an intensive investigation is also conducted on licensed applications and free web servers used in in silico studies. The current review is an up-to-date guide for researchers who plan to conduct computational studies with MDR transporter proteins.
Background
Cancer stem cells (CSCs) are a small subpopulation of tumor cells with the capability of self‐renewal and drug resistance, leading to tumor progression and disease relapse. Our study aimed to investigate the antitumor effect of berbamine, extracted from berberis amurensis, on prostate CSCs.
Methods
Sphere formation was used to collect prostate CSCs. The viability, proliferation, invasion, migration, and apoptosis assays were used to evaluate the antitumor effect of berbamine on prostate CSCs. Prostate CSC markers were analyzed by flow cytometry and qRT‐PCR. Small RNA sequencing analysis was conducted to analyse miRNAs. Exosomes were extracted using the ExoQuick‐TC kit and verified by testing exosomal markers using western blot.
Results
Berbamine targets prostate CSCs. Additionally, berbamine enhanced the antitumor effect of cabazitaxel, a second‐line chemotherapeutic drug for advanced prostate cancer, and re‐sensitized Cabazitaxel‐resistant PCa cells (CabaR‐DU145) to cabazitaxel by inhibiting ABCG2, CXCR4, IGF2BP1, and p‐STAT3. Berbamine enhanced the expression of let‐7 miRNA family and miR‐26b and influenced the downstream targets IGF2BP1 and p‐STAT3, respectively. Silencing CXCR4 and ABCG2 downregulated the expression of IGF2BP1 and p‐STAT3, respectively. Importantly, berbamine enhanced also levels of exosomal let‐7 family and miR‐26b, suggesting that berbamine possibly influences the expression of let‐7 family and miR‐26b through exosome delivery. Exosomes derived from berbamine‐treated CabaR‐DU145 cells re‐sensitized the cells to cabazitaxel.
Conclusion
Berbamine enhanced the toxic activity of cabazitaxel and reversed cabazitaxel resistance potentially through CXCR4/exosomal let‐7/IGF2BP1 and ABCG2/exosomal miR‐26b/p‐STAT3 axes.
