Table 1.

Metformin targets multiple signaling pathways in cancer

Proposed mechanism	Functions	Tumor type/model	References
AMPK-dependent	Inhibition of cell mitosis and proliferation	Human carcinoma tissues and human cancer cell lines	[29]
	Up-regulation of the p53–p21 axis and down-regulation of cyclin D1	T-cell acute lymphoblastic leukemia	[30–32]
	DNA synthesis	Pancreatic cancer	[34]
	Growth inhibition and G0/G1 cell cycle arrest	Lymphoma cells	[36]
	Cell apoptosis	Acute lymphoblastic leukemia	[36]
	Suppression of multidrug resistance 1 gene activation	Breast cancer	[37]
AMPK-independent	REDD1, a negative regulator of mTOR, mediates cell cycle arrest and cyclin D1 decrease	Prostate cancer cells	[39]
	Induced apoptosis	Human ovarian cancer cells	[40]
Suppression of mTOR	Inhibition of global protein synthesis and cell proliferation	Breast cancer	[54–56]
	Repression of oncogenic mRNA translation	Leukemia	[30, 32]
		Lung cancer	[59, 60]
	Inhibition of cell growth and induction of apoptosis	Breast cancer	[61, 62]
	Prevents the development of carcinogen-induced premalignant lesions	Oral squamous cell carcinoma	[63]
	Induction of autophagy	Lymphoma	[36]
	Inhibits growth and decreases resistance to anoikis	Thyroid cancer	[35, 64]
	Inhibits skin tumor promotion	In overweight and obese mice with papilloma and squamous cell carcinoma	[65]
	Suppresses HER2 oncoprotein overexpression	Breast cancer	[101]
Suppression of IGF signaling	Prevents androgen-mediated IGF-1R up-regulation; reduces cell proliferation, invasion, and clonogenic capacity	Prostate cancer cells	[82]
	Reduces the circulating levels of insulin and IGF-1; blocks cell growth and proliferation	A tobacco carcinogen-induced lung cancer model in A/J mice	[60]
AMPK-induced phosphorylation of insulin receptor substrate-1	Switches off IGF-1-induced activation of Akt/Tsc1/mTOR	Human pancreatic cancer cells, breast cancer cells	[83–85]
Activation of AMPK	Disruption of crosstalk between insulin/IGF-1R and GPCR signaling	Pancreatic cancer	[86]
Activation of the JNK/p38 MAPK pathway	Apoptosis-mediated effect	Lung cancer cells	[100]
The MAPK signaling pathway	Synergistic effects of metformin in combination with gefitinib	Lung cancer	[59, 91]
	Blocks tumor cells migration and invasion and inhibits MMP-9 activation	Human fibrosarcoma	[92]
	Inhibits cell growth and colony formation and induces cell cycle arrest	Breast cancer	[93–96]
	Blocks survival signals	Prostate cancer	[97]
		Endometrial cancer	[98]
Inhibition of the NF-κB pathway	Halts proliferation of cancer cells and causes death; sensitizes to chemotherapeutic reagents	Inflammation-associated tumors	[107]
Repression of the NF-κB and mTOR signaling pathways	Growth inhibition	Cutaneous squamous cell carcinoma	[99]
Inhibition of CSCs	Inhibits cellular transformation and selectively kills cancer stem cells	Preclinical breast cancer models	[119]
Down-regulation of CSC markers	Inhibits cell proliferation, migration, and invasion	Pancreatic cancer	[121, 122]
Targeting CSCs and mTOR	Inhibits esophageal cancer cell growth and sensitizes cells to 5-FU cytotoxic effects	Esophageal cancer cells	[123]
Selective suppression of NF-κB nuclear localization and STAT3 activity	Inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in CSCs	Breast cancer, prostate cancer, and melanoma cell lines	[126]

AMPK adenosine monophosphate-activated protein kinase, REDD1 regulated in development and DNA damage 1, mTOR mammalian target of rapamycin, HER2 human epidermal growth factor receptor-2, IGF insulin-like growth factor, GPCR G protein-coupled receptor, IGF-1 insulin-like growth factor-1, JNK c-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, MMP-9 matrix metallopeptidase-9, NF-κB nuclear factor kappaB, CSCs cancer stem cells, 5-FU 5-fluorouracil, STAT3 signal transducer and activator of transcription 3