Metformin against Cancer Stem Cells through the Modulation of Energy Metabolism: Special Considerations on Ovarian Cancer

Table 1

Preclinical studies of metformin targeting metabolism of ovarian cancer cells and/or ovarian CSCs.

Agent or drug (dosage)	CSCs enriched	Alone	Combination with other drugs	Mechanism of action	Reference
Metformin; (0.02 mmol/L in vitro)	No	No significant loss of viability or change in cell cycle	Improvement of cytotoxic response to carboplatin	<--->	[63]
Metformin; (5 mmol/L in vitro),; PEITC; (5 µmol/L in vitro)	No	Inhibition of growth in vitro	Combination with PEITC increases cell death in vitro	ROS generation	[62]
Metformin; (5 mmol/L in vitro)	No	Induced apoptosis in vitro	Combination with cisplatin enhances apoptosis	AMPK-independent, downregulating Bcl-2/Bcl-xL, upregulating Bax/Bad	[65]
Metformin; (100–200 mg/kg in vivo)	No	Inhibition of ovarian tumor growth, proliferation, metastasis, and angiogenesis in vivo	Combination with cisplatin reduces tumor growth	AMPK/mTOR, antiangiogenic effect	[64]
Metformin; (5 mmol/L in vitro)	No	Inhibition of proliferation in vitro	<--->	Cell cycle arrest, AMPK/mTOR and AMPK independent pathway	[66]
Metformin; (5–50 mmol/L in vitro)	No	Inhibition of proliferation in vitro	Improvement of cytotoxic response to cisplatin	AMPK/mTOR	[67]
Metformin; (0.3 mmol/L in vitro, 150 mg/kg in vivo)	ALDH+ cells	Inhibition of ovarian CSC/TIC growth in vitro, nonsignificant decreases in tumor growth in vivo	Combination with cisplatin restricts tumor growth in vivo	<--->	[13]

CSC, cancer stem cell; ROS, reactive oxygen species; AMPK, adenosine monophosphate-activated protein kinase; mTOR, mammalian target of rapamycin; ALDH, aldehyde dehydrogenase; PEITC, phenethyl isothiocyanate; TIC, tumor initiating cell. Modified and adapted with permission from reference [15].