Table 1: Preclinical studies of metformin targeting metabolism of ovarian cancer cells and/or ovarian CSCs.

Agent or drug (dosage)CSCs enrichedAloneCombination with other drugsMechanism of actionReference

Metformin
(0.02 mmol/L in vitro)
NoNo significant loss of viability or change in cell cycleImprovement of cytotoxic response to carboplatin< > [63]

Metformin
(5 mmol/L in vitro),
PEITC
(5 µmol/L in vitro)
NoInhibition of growth in vitroCombination with PEITC increases cell death in vitroROS generation [62]

Metformin
(5 mmol/L in vitro)
NoInduced apoptosis in vitroCombination with cisplatin enhances apoptosisAMPK-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 vivoCombination with cisplatin reduces tumor growthAMPK/mTOR, antiangiogenic effect [64]

Metformin
(5 mmol/L in vitro)
NoInhibition of proliferation in vitro< >Cell cycle arrest, AMPK/mTOR and AMPK independent pathway [66]

Metformin
(5–50 mmol/L in vitro)
NoInhibition of proliferation in vitroImprovement of cytotoxic response to cisplatinAMPK/mTOR [67]

Metformin
(0.3 mmol/L in vitro, 150 mg/kg in vivo)
ALDH+ cellsInhibition of ovarian CSC/TIC growth in vitro, nonsignificant decreases in tumor growth in vivoCombination 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].