Metformin targets ovarian cancer stem cells in vitro and in vivo

Abstract

Purpose-Studies in non-gynecologic tumors indicate that metformin inhibits growth of cancer stem cells (CSC). Diabetic patients with ovarian cancer who are taking metformin have better outcomes than those not taking metformin. The purpose of this study was to directly address the impact of metformin on ovarian CSC. Methods-The impact of metformin on ovarian cancer cell line growth and viability was assessed with trypan blue staining. Aldehyde dehydrogenase (ALDH) expressing CSC were quantified using FACS®. Tumor sphere assays were performed to determine the impact of metformin on cell line and primary human ovarian tumor CSC growth in vitro. In vivo therapeutic efficacy and the anti-CSC effects of metformin were confirmed using both tumor cell lines and ALDH(+) CSC tumor xenografts. Results-Metformin significantly restricted the growth of ovarian cancer cell lines in vitro. This effect was additive with cisplatin. FACS analysis confirmed that metformin reduced ALDH(+) ovarian CSC. Consistent with this, metformin also inhibited the formation of CSC tumor spheres from both cell lines and patient tumors. In vivo, metformin significantly increased the ability of cisplatin to restrict whole tumor cell line xenografts. In addition, metformin significantly restricted the growth of ALDH(+) CSC xenografts. This was associated with a decrease in ALDH(+) CSC, cellular proliferation, and angiogenesis. Conclusions-Metformin can restrict the growth and proliferation of ovarian cancer stem cells in vitro and in vivo. This was true in cell lines and in primary human CSC isolates. These results provide a rationale for using metformin to treat ovarian cancer patients.

Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning

“…Several in vitro and in vivo pre-clinical investigations have detected a growth-static effect of metformin also in gynecological malignancies, including ovarian cancer (40,(48)(49)(50)(51)(52)(53)(54)(55), endometrial cancer (23-25, 55, 59-65, 67, 72, 74, 89) and breast cancer (12,17,22,38,130,131,134,135), mainly due to the effects of drug on the IGF system and different intracellular signaling transduction pathways .…”

“…Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells [CSC]s, and acts together with chemotherapy to block tumor growth in different cancers, such as breast cancer , prostate cancer, lung cancer, and ovarian cancer (38)(39)(40).…”

Metformin inhibits the proliferation, metastasis, and cancer stem-like sphere formation in osteosarcoma MG63 cells in vitro

“…Metformin, an oral biguanide medicine widely used for type 2 diabetes treatment, inhibited growth and survival of tumor cells and tumor stem cells in multiple malignances, which has been reported in numerous studies [18,[22][23][24][25][26]34]. In our study, we used OS MG63 cell line to examine the effects of metformin on osteosarcoma cell growth, migration, and invasion in vitro.…”

“…Recent evidence indicate that metformin may reduce the risk of cancer in patients with type 2 diabetes [19][20][21]. Furthermore, in vivo and in vitro studies have demonstrated that metformin inhibits tumor cells and tumor stem cell growth and survival in numerous tumors [22][23][24][25][26]. Metformin induces the LKB1-mediated activation of AMPK which in turn inhibits mammalian target of rapamycin (mTOR) signaling and then affects protein synthesis and proliferation in various cancer cell lines [27].…”

Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer

“…Interestingly, metformin intake has been shown to reduce ovarian cancer related mortality. It has also been shown that metformin enhances the chemo-sensitivity of patients with ovarian cancer [7][8][9]. However, the mechanism underlying the anticancer effects of metformin in the ovarian cancer cells is not fully understood.…”