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.

Bulk pancreatic cancer cells can convert into cancer stem cells(CSCs) in vitro and 2 compounds can target these CSCs

“…CD133+ colorectal CSCs, 22 ovarian CSCs 23 and human glioblastoma tumor-initiating cells. 24 Curcumin, a food spice derived from turmeric, can suppress the self-renewal of human breast CSCs, 25,26 colon CSCs, 27 laryngeal carcinoma CSCs 28 and rat C6 glioma SP cells.…”

Metformin in Ovarian Cancer

“…Metformin down regulates the expression of a cancer-stemness marker CD44 and other stemness markers, including Nanog, Oct-4, cMyc and, ALDH in these cancer cells [19]. Metformin significantly restricted the growth of ovarian cancer cell lines in vitro.…”

Ovarian cancer stem cells: A target for oncological therapy

“…[25][26][27][28] Numerous studies have shown that the favorable effect of metformin in the development and course of malignant tumors, including ovarian cancer, may be linked to its inhibitory effect on CSCs. [29][30][31] Studies on the SKOV3 and A2780 cell lines of ovarian cancers conducted by Zhang et al demonstrated that low doses of metformin selectively inhibit CSCs with markers CD44+ and CD117+, and inhibit epithelial mesenchymal transition (EMT). 32 Epithelial mesenchymal transition is linked to the activity of transcription factors and the activation of several genes, resulting in the inhibition of apoptosis and an increased mobility of cells, linked to metastases.…”

“…29 The authors expressed the opinion that the mechanism of its action involved a reduction in the CSC population with ALDH1+ marker, reduced cell proliferation and inhibited angiogenesis. They argued that the results provided rationale for the application of metformin in patients treated due to ovarian cancer.…”