From: 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 | ||
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 | |
Repression of oncogenic mRNA translation | Leukemia | ||
Lung cancer | |||
Inhibition of cell growth and induction of apoptosis | Breast cancer | ||
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 | ||
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 | |
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 | |
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 | ||
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 | |
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] |