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Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models.

ABSTRACT: Acquired resistance to chemo-drugs remains a major obstacle to successful cancer therapy. Metformin, a well-documented drug for treating type II diabetes, was recently proposed as a novel agent for tumor treatment. In this study, we found that metformin suppressed MCF7/ADR, a doxorubicin-resistant breast cancer cell line, and acted synergistically with doxorubicin by reversing drug-resistant phenotypes both in vitro and in vivo. Metformin alone dose-dependently inhibited tumor growth, especially the stressful tumor microenvironment of glucose deficiency, and the cytotoxicity of metformin was markedly enhanced by increasing ROS production and ATP depletion. In addition, we found that metformin showed synergistic activity with doxorubicin against MCF7/ADR. Metformin increased nuclear doxorubicin accumulation and overcame drug resistance by down-regulating drug-resistant genes such as P-glycoprotein (Pgp). Metformin alone markedly inhibited MCF7/ADR tumor xenografts and demonstrated synergistic activity with doxorubicin in vivo by eliminating Ki67-positive cancer cells. In addition, metformin suppressed Pgp expression in vivo. In conclusion, our results suggested that metformin could potentially be used in the treatment of chemo-resistant tumors and could restore doxorubicin sensitivity.

SUBMITTER: Li Y

PROVIDER: S-EPMC5788630 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models.

Li Ying Y Wang Meng M Zhi Pei P You Jian J Gao Jian-Qing JQ

Oncotarget 20171208 2

Acquired resistance to chemo-drugs remains a major obstacle to successful cancer therapy. Metformin, a well-documented drug for treating type II diabetes, was recently proposed as a novel agent for tumor treatment. In this study, we found that metformin suppressed MCF7/ADR, a doxorubicin-resistant breast cancer cell line, and acted synergistically with doxorubicin by reversing drug-resistant phenotypes both <i>in vitro</i> and <i>in vivo</i>. Metformin alone dose-dependently inhibited tumor grow ...[more]

PMID: 29416762

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Project description:Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA2021 in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA2021 withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA2021 contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA2021, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA2021 increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA2021 alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA2021 bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA2021 stably interacted with Hsp90α more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA2021 showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-𝜅B) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA2021 to confirm its anticancer capabilities.

Dataset Information

Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models.

Publications

Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models.

Similar Datasets

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