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].