Abstract
Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that occurs when the body’s regulation of sugar is impaired
Aging is a biological phenomenon in all organisms and can be characterized by an accumulation of various deleterious changes with time associated with an increased risk of susceptibility to disease and death
Kawakita and his colleagues indicated that metformin can inhibit Dipeptidyl peptidase-4 (DPP-4) inhibitor (KR62436)-induced metastasis of the triple-negative breast cancer (TNBC) cell line MDA-MB231 through the suppression of mammalian target of rapamycin (mTOR), which is accompanied by the downregulation of α-SMA and the upregulation of E-cadherin [96]
Summary
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that occurs when the body’s regulation of sugar (glucose) is impaired. Apart from the AMPK pathway, emerging evidence has reported that metformin can regulate AMPK-independent pathways, such as autophagy, oxidative stress and ER stress, to prevent retinal cells from vascular abnormalities, apoptosis, and cell senescence, which suppresses the development of diabetic retinopathy (DR). According to a statistical analysis by Kim, during a mean 5.8 years of follow-up, the incidence of cancer among patients with T2DM was 21.8 and 13.2 per 1000 person-years in the no metformin and metformin groups, respectively. This finding indicated that the administration of metformin to patients with T2DM could reduce the risk of developing cancer [8]. We will elucidate the effects of metformin against aging, DR and cancer through diverse mechanisms
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