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Overcoming cisplatin resistance by targeting the MTDH-PTEN interaction in ovarian cancer with sera derived from rats exposed to Guizhi Fuling wan extract.

ABSTRACT: BACKGROUND:The well-known traditional Chinese herbal formula Guizhi Fuling Wan (GFW) was recently reported to improve the curative effects of chemotherapy for ovarian cancer with few clinical side effects. The present study aimed to investigate the reversal mechanism of sera derived from rats exposed to Guizhi Fuling Wan extract (GFWE) in cisplatin-resistant human ovarian cancer SKOV3/DDP cells; the proteins examined included phosphatase and tensin homolog (PTEN) and metadherin (MTDH), and the possible protein interaction between PTEN and MTDH was explored. METHODS:GFWE was administered to healthy Wistar rats, and the sera were collected after five days. The PubMed and CNKI databases were searched for literature on the bioactive blood components in the sera. The systemsDock website was used to predict potential PTEN/MTDH interactions with the compounds. RT-qPCR, western blotting, and immunofluorescence analyses were used to analyze the mRNA and protein levels of MTDH and PTEN. Laser confocal microscopy and coimmunoprecipitation (co-IP) were used to analyze the colocalization and interaction between MTDH and PTEN. RESULTS:Sixteen bioactive compounds were identified in GFWE sera after searching the PubMed and CNKI databases. The systemsDock website predicted the potential PTEN/MTDH interactions with the compounds. RT-qPCR, western blotting, and immunofluorescence analyses showed decreased MTDH expression and increased PTEN expression in the sera. Laser confocal microscopy images and coimmunoprecipitation (co-IP) analyses demonstrated that a colocalization and interaction occurred between MTDH and PTEN, and the addition of the sera changed the interaction status. CONCLUSIONS:GFWE restored sensitivity to cisplatin by inhibiting MTDH expression, inducing PTEN expression, and improving the interaction between MTDH and PTEN in SKOV3/DDP cells, and these proteins and their interaction may serve as potential targets for cancer treatment. The sera may represent a new source of anticancer compounds that could help to manage chemoresistance more efficiently and safely.

SUBMITTER: Han L

PROVIDER: S-EPMC7076886 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Overcoming cisplatin resistance by targeting the MTDH-PTEN interaction in ovarian cancer with sera derived from rats exposed to Guizhi Fuling wan extract.

Han Li L Cao Xueyun X Chen Zhong Z Guo Xiaojuan X Yang Lei L Zhou Yubing Y Bian Hua H

BMC complementary medicine and therapies 20200217 1

<h4>Background</h4>The well-known traditional Chinese herbal formula Guizhi Fuling Wan (GFW) was recently reported to improve the curative effects of chemotherapy for ovarian cancer with few clinical side effects. The present study aimed to investigate the reversal mechanism of sera derived from rats exposed to Guizhi Fuling Wan extract (GFWE) in cisplatin-resistant human ovarian cancer SKOV3/DDP cells; the proteins examined included phosphatase and tensin homolog (PTEN) and metadherin (MTDH), a ...[more]

PMID: 32066429

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Project description:AimThis study aimed to predict the key targets and endocrine mechanisms of Guizhi Fuling Wan (GZFLW) in treating adenomyosis (AM) through network pharmacology, molecular docking, and animal experiment verification.MethodsThe related ingredients and targets of GZFLW in treating AM were screened out using TCMSP, BATMAN-TCM, SwissTargetPrediction, and PubChem Database. Then, the protein-protein interaction (PPI) analysis and the network of compound-hub targets were constructed. At the same time, the key targets were uploaded to the Metascape Database for KEGG pathway enrichment analysis. After that, the molecular docking technology of the main active components and hub targets was performed. Furthermore, animal experiments were used to verify the results of network pharmacology analysis.ResultsA total of 55 active ingredients of GZFLW and 44 overlapping targets of GZFLW in treating AM were obtained. After screening, 25 hub targets were collected, including ESR1, EGF, and EGFR. Then, the KEGG pathway enrichment analysis results indicated that the endocrine therapeutic mechanism of GZFLW against AM is mainly associated with the estrogen signaling pathway, endocrine resistance, and an EGFR tyrosine kinase signaling pathway. Then, molecular docking showed that the significant compounds of GZFLW had a strong binding ability with ERα and EGFR. More importantly, the animal experiments confirmed that the GZFLW could downregulate the abnormal infiltration of the endometrial epithelium into the myometrium and had no interference with the normal sexual cycle. This effect may be directly related to intervening the local estrogen signaling pathway of the endometrial myometrial interface (EMI). It may also be associated with the myometrium cells' estrogen resistance via GPER/EGFR signaling pathway.ConclusionThe endocrine mechanism of GZFLW in treating AM was explored based on network pharmacology, molecular docking, and animal experiments, which provided a theoretical basis for the clinical application of GZFLW.

Project description:BackgroundGuizhi Fuling Wan (GZFLW) is a widely used classical Chinese herbal formulae prescribed for the treatment of endometriosis (EMs). This study aimed to predict the key targets and mechanisms of GZFLW in the treatment of EMs by network pharmacology and molecular docking.MethodsFirstly, related compounds and targets of GZFLW were identified through the TCMSP, BATMAN-TCM and CASC database. Then, the EMs target database was built by GeneCards. The overlapping targets between GZFLW and EMs were screened out, and then data of the PPI network was obtained by the STRING Database to analyze the interrelationship of these targets. Furthermore, a topological analysis was performed to screen the hub targets. After that, molecular docking technology was used to confirm the binding degree of the main active compounds and hub targets. Finally, the DAVID database and Metascape database were used for GO and KEGG enrichment analysis.ResultsA total of 89 GZFLW compounds and 284 targets were collected. One hundred one matching targets were picked out as the correlative targets of GZFLW in treating EMs. Among these, 25 significant hub targets were recognized by the PPI network. Coincidently, molecular docking simulation indicated that the hub targets had a good bonding activity with most active compounds (69.71%). Furthermore, 116 items, including the inflammatory reaction, RNA polymerase, DNA transcription, growth factor activity, and steroid-binding, were selected by GO enrichment analysis. Moreover, the KEGG enrichment analysis results included 100 pathways focused on the AGE-RAGE pathway, HIF pathway, PI3K Akt pathway, MAPK pathway, and TP53 pathway, which exposed the potential mechanisms of GZFLW in treating EMs. Also, the MTT colorimetric assay indicated that the cell proliferation could be inhibited by GZFLW. Compared with the control group, the protein levels of P53, BAX, and caspase3 in the drug groups were all increased in Western blotting results. The results of flow cytometry showed that the percentage of apoptotic cells in the GZFLW group was significantly higher than that in the control group.ConclusionThrough the exploration of network pharmacology and molecular docking technology, GZFLW has a therapeutic effect on EMs through multi-target mechanism. This study provided a good foundation for further experimental research.

Project description:Polycystic ovary syndrome (PCOS) is a common endocrine disease with reproductive dysfunction and metabolic disorder in women of childbearing age. Gastrointestinal microbiome contributes to PCOS through mediating insulin resistance. Guizhi Fuling Wan, Chinese herbal medicine, can treat PCOS with insulin resistance (PCOS-IR), but the underlying mechanism is not clear. The aim of this study was to characterize the exact mechanism of Guizhi Fuling Wan action and whether it is related to the regulation of intestinal flora structure. We induced PCOS-IR rat model by means of letrozole sodium carboxymethyl cellulose (CMC-na) solution combined with high-fat emulsion administration and randomly divided it into blank control group (K), model control group (M), low dose of Guizhi Fuling Wan group (D), middle dose of Guizhi Fuling Wan group (Z), high dose of Guizhi Fuling Wan group (G) and positive drug (Metformin) control group (Y). After 36 days of modeling and treatment, serum and stool samples from all rats were collected for a follow-up analysis. The data display that, compared with K group, elevated testosterone and HOMA-IR, turbulent estrous cycles and polycystic ovaries in M group, indicating the PCOS-IR rat model is successfully established. Increased fasting insulin is associated with higher inflammation(plasma TNF-α, IL-6, and HS-CPR concentration were determined) in M group, and the altered intestinal flora (compared with the K group, in M group the relative abundance of Alloprevotella was decreased significantly, while the relative abundance of Lachnospiraceae UCG-008, Lachnospiraceae NK4A136, Lactobacillus, Ruminiclostridium 9, and Ruminococcaceae UCG-003 was increased significantly) induced the secretion of inflammatory markers. On the other hand, Guizhi Fuling Wan can alleviate inflammation, improve insulin resistence: Lower inflammation decreased fasting insulin can be seen in G group compared with M group, this effect is related to the regulating effect of Guizhi Fuling Wan on intestinal flora (in G group, the relative abundance of Alloprevotella, Ruminococcaceae UCG-003, and Lachnospiraceae UCG-008 was increased significantly, compared with M group). This research demonstrates Guizhi Fuling Wan improve insulin resistance in polycystic ovary syndrome with the underlying mechanism of regulating intestinal flora to control inflammation. It would be useful to promote the therapeutic effect of Guizhi Fuling Wan on PCOS-IR.

Project description:Dysmenorrhea refers to a kind of uterine cramping pain that occurs in women during the period of menstrual. Guizhi Fuling Capsules are mainly used for the treatment of various pain syndromes and especially effective in treating primary dysmenorrhea. However, the research on its modern pharmacology and mechanism of action have not been thoroughly carried out. It is not clear about the main active ingredients, potential targets and metabolic pathways involved in its efficacy. Therefore, this research project employed estradiol benzoate sensitization combined with oxytocin pain to construct the cold coagulation syndrome dysmenorrhea model, observed the anti-dysmenorrhea effect of Guizhi Fuling Capsules, and used the metabolomics to explore its mechanism. The results showed that Guizhi Fuling Capsules could considerably reduce the number of writhing times in dysmenorrhea rats, increasing the level of PGE2 and β-EP and reducing the contents of PGF2α in rat serum. Pathological sections of uterus and ovaries also showed that Guizhi Fuling Capsules could significantly relieve endometrial hyperplasia and improve ovarian function. The LC/MS-based metabolomics of rat uterine indicated that the model group has a great deviation from the control group. Compared with the model group, the Guizhi Fuling Capsules group had a tendency to shift to the control group, and the main metabolic changes was mainly concentrated on saturated and unsaturated fatty acids. Among them, arachidonic acid is in a pivotal position, and the expression of its rate-limiting enzyme (COX-2) involved in its cyclooxygenase metabolic pathway was significantly up-regulated in the model group, but significantly decreased after the intervention of Guizhi Fuling Capsules. In conclusion, Guizhi Fuling Capsules can effectively relieve primary dysmenorrhea, and this effect may be attributed to the regulation effects of Guizhi Fuling Capsules on endogenous metabolism, such as inhibiting arachidonic acid converted to prostaglandins through downregulate the expression of COX-2, which plays an anti-inflammatory effect.

Dataset Information

Overcoming cisplatin resistance by targeting the MTDH-PTEN interaction in ovarian cancer with sera derived from rats exposed to Guizhi Fuling wan extract.

Publications

Overcoming cisplatin resistance by targeting the MTDH-PTEN interaction in ovarian cancer with sera derived from rats exposed to Guizhi Fuling wan extract.

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