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Cellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer: A Translational In Vitro-In Silico Model.

ABSTRACT: Doxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of the drug. Resveratrol (Rsv) has been tested as an adjuvant in mammary malignancies. However, the cellular and molecular mechanisms underlying the effects of cotreatment with Doxo and Rsv in breast cancer are poorly understood. Here, we combined in vitro and in silico analysis to characterize these mechanisms. In vitro, we employed a clinically relevant experimental design consisting of acute (24?h) treatment followed by 15 days of analysis. Acute Rsv potentiated the long-lasting effect of Doxo through the induction of apoptosis and senescence. Cells that survived to the cotreatment triggered high levels of autophagy. Autophagy inhibition during its peak of activation but not concomitant with Doxo+Rsv increased the long-term toxicity of the cotreatment. To uncover key proteins potentially associated with in vitro effects, an in silico multistep strategy was implemented. Chemical-protein networks were predicted based on constitutive gene expression of MCF7 cells and interatomic data from breast cancer. Topological analysis, KM survival analysis, and a quantitative model based on the connectivity between apoptosis, senescence, and autophagy were performed. We found seven putative genes predicted to be modulated by Rsv in the context of Doxo treatment: CCND1, CDH1, ESR1, HSP90AA1, MAPK3, PTPN11, and RPS6KB1. Six out of these seven genes have been experimentally proven to be modulated by Rsv in cancer cells, with 4 of the 6 genes in MCF7 cells. In conclusion, acute Rsv potentiated the long-term toxicity of Doxo in breast cancer potentially through the modulation of genes and mechanisms involved in Doxo resistance. Rational autophagy inhibition potentiated the effects of Rsv+Doxo, a strategy that should be further tested in animal models.

SUBMITTER: Vargas JE

PROVIDER: S-EPMC7654215 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer: A Translational In Vitro-In Silico Model.

Vargas José Eduardo JE Puga Renato R Lenz Guido G Trindade Cristiano C Filippi-Chiela Eduardo E

Oxidative medicine and cellular longevity 20201101

Doxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of the drug. Resveratrol (Rsv) has been tested as an adjuvant in mammary malignancies. However, the cellular and molecular mechanisms underlying the effects of cotreatment with Doxo and Rsv in breast cancer are poorly understood. Here, we combined ...[more]

PMID: 33204396

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Project description:The use of chemopreventive natural compounds represents a promising strategy in the search for novel therapeutic agents in cancer. Resveratrol (3,4',5-trans-trihydroxystilbilene) is a dietary polyphenol found in fruits, vegetables and medicinal plants that exhibits chemopreventive and antitumor effects. In this study, we searched for modulated proteins with preventive or therapeutic potential in MCF-7 breast cancer cells exposed to resveratrol. Using two-dimensional electrophoresis we found significant changes (FC >2.0; p?0.05) in the expression of 16 proteins in resveratrol-treated MCF-7 cells. Six down-regulated proteins were identified by tandem mass spectrometry (ESI-MS/MS) as heat shock protein 27 (HSP27), translationally-controlled tumor protein, peroxiredoxin-6, stress-induced-phosphoprotein-1, pyridoxine-5'-phosphate oxidase-1 and hypoxanthine-guanine phosphoribosyl transferase; whereas one up-regulated protein was identified as triosephosphate isomerase. Particularly, HSP27 overexpression has been associated to apoptosis inhibition and resistance of human cancer cells to therapy. Consistently, we demonstrated that resveratrol induces apoptosis in MCF-7 cells. Apoptosis was associated with a significant increase in mitochondrial permeability transition, cytochrome c release in cytoplasm, and caspases -3 and -9 independent cell death. Then, we evaluated the chemosensitization effect of increasing concentrations of resveratrol in combination with doxorubicin anti-neoplastic agent in vitro. We found that resveratrol effectively sensitize MCF-7 cells to cytotoxic therapy. Next, we evaluated the relevance of HSP27 targeted inhibition in therapy effectiveness. Results evidenced that HSP27 inhibition using RNA interference enhances the cytotoxicity of doxorubicin. In conclusion, our data indicate that resveratrol may improve the therapeutic effects of doxorubicin in part by cell death induction. We propose that potential modulation of HSP27 levels using natural alternative agents, as resveratrol, may be an effective adjuvant in breast cancer therapy.

Project description:BackgroundReactive oxygen species (ROS)-responsive drug delivery systems (DDSs) are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy. However, it is challenging to achieve spatially and temporally controllable and accurate drug release in tumor sites based on ROS-responsive DDSs. To solve this problem, we designed a nanosystem combined photodynamic therapy (PDT) and ROS-responsive chemotherapy.MethodsIndocyanine green (ICG), an ROS trigger and photosensitizer, and pB-DOX, a ROS-responsive prodrug of doxorubicin (DOX), were coencapsulated in polyethylene glycol modified liposomes (Lipo/pB-DOX/ICG) to construct a combination therapy nanosystem. The safety of nanosystem was assessed on normal HEK-293 cells, and the cellular uptake, intracellular ROS production capacity, target cell toxicity, and combined treatment effect were estimated on human breast cancer cells MDA-MB-231. In vivo biodistribution, biosafety assessment, and combination therapy effects were investigated based on MDA-MB-231 subcutaneous tumor model.ResultsCompared with DOX·HCl, Lipo/pB-DOX/ICG showed higher safety on normal cells. The toxicity of target cells of Lipo/pB-DOX/ICG was much higher than that of DOX·HCl, Lipo/pB-DOX, and Lipo/ICG. After endocytosis by MDA-MB-231 cells, Lipo/pB-DOX/ICG produced a large amount of ROS for PDT by laser irradiation, and pB-DOX was converted to DOX by ROS for chemotherapy. The cell inhibition rate of combination therapy reached up to 93.5 %. After the tail vein injection (DOX equivalent of 3.0 mg/kg, ICG of 3.5 mg/kg) in mice bearing MDA-MB-231 tumors, Lipo/pB-DOX/ICG continuously accumulated at the tumor site and reached the peak at 24 h post injection. Under irradiation at this time point, the tumors in Lipo/pB-DOX/ICG group almost disappeared with 94.9 % tumor growth inhibition, while those in the control groups were only partially inhibited. Negligible cardiotoxicity and no treatment-induced side effects were observed.ConclusionsLipo/pB-DOX/ICG is a novel tool for on-demand drug release at tumor site and also a promising candidate for controllable and accurate combinatorial tumor therapy.

Dataset Information

Cellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer: A Translational In Vitro-In Silico Model.

Publications

Cellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer: A Translational In Vitro-In Silico Model.

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