Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma

Abstract

BackgroundTamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy.MethodsThe efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay.ResultsWhen metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo.ConclusionThe present work shows that metformin and tamoxifen additively inhibited the growth and augmented the apoptosis of ER-positive breast cancer cells. It provides leads for future research on this drug combination for the treatment of ER-positive breast cancer.

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria

“…Similar to CYP3A4 silencing (Mitra et al, 2011), metformin was also found to inhibit Stat3 signaling in breast cancer (Deng et al, 2012), suggesting that metformin might inhibit CYP3A4 mediated EET biosynthesis. Metformin inhibits mammary tumor growth (Iliopoulos et al, 2011; Ma et al, 2014), suppresses mitochondrial respiration (Wheaton et al, 2014) and can be modified easily by click chemistry using the cyano-guanidine condensation reaction (Choi et al, 2016; Kim et al, 2012b; Row et al, 2016). Nonetheless, metformin lacks potency, particularly in ER+HER2− breast cancer (Ma et al, 2014), and potency can’t yet be improved by structure activity studies, because a structural target for metformin remains to be identified.…”

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

“…30 Cells were seeded into 6-well plates (1£10 3 cells per well) and treated with metformin at various concentrations (0 mM, 0.625 mM, 2.5 mM, or 10 mM). After 14 days, the resulting colonies were fixed with 4% cold paraformaldehyde for 15 min and stained with crystal violet (Beyotime C0121) for 15 min at room temperature.…”

Aspirin and metformin exhibit antitumor activity in murine breast cancer

“…Traditionally, patients with type 2 diabetes mellitus and cardiovascular diseases are treated with aspirin and metformin (1)(2)(3). In recent years, both drugs have been reported to decrease the risk of several types of cancers, including breast cancer (4)(5)(6)(7)(8)(9)(10).…”