Article

Metformin in cancer: translational challenges.

Division of Signalling Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2M9.
Journal of Molecular Endocrinology (impact factor: 3.48). 02/2012; 48(3):R31-43. DOI:10.1530/JME-12-0007
Source: PubMed

ABSTRACT The anti-diabetic drug metformin is rapidly emerging as a potential anti-cancer agent. Metformin, effective in treating type 2 diabetes and the insulin resistance syndromes, improves insulin resistance by reducing hepatic gluconeogenesis and by enhancing glucose uptake by skeletal muscle. Epidemiological studies have consistently associated metformin use with decreased cancer incidence and cancer-related mortality. Furthermore, numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to an explosion of interest in evaluating this agent in human cancer. The effects of metformin on circulating insulin levels indicate a potential efficacy towards cancers associated with hyperinsulinaemia; however, metformin may also directly inhibit tumour growth. In this review, we describe the mechanism of action of metformin and summarise the epidemiological, clinical and preclinical evidence supporting a role for metformin in the treatment of cancer. In addition, the challenges associated with translating preclinical results into therapeutic benefit in the clinical setting will be discussed.

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    Article: Metformin is synthetically lethal with glucose withdrawal in cancer cells.
    Javier A Menendez, Cristina Oliveras-Ferraros, Sílvia Cufí, Bruna Corominas-Faja, Jorge Joven, Begoña Martin-Castillo, Alejandro Vazquez-Martin
    [show abstract] [hide abstract]
    ABSTRACT: Glucose deprivation is a distinctive feature of the tumor microecosystem caused by the imbalance between poor supply and an extraordinarily high consumption rate. The metabolic reprogramming from mitochondrial respiration to aerobic glycolysis in cancer cells (the "Warburg effect") is linked to oncogenic transformation in a manner that frequently implies the inactivation of metabolic checkpoints such as the energy rheostat AMP-activated protein kinase (AMPK). Because the concept of synthetic lethality in oncology can be applied not only to genetic and epigenetic intrinsic differences between normal and cancer cells but also to extrinsic ones such as altered microenvironment, we recently hypothesized that stress-energy mimickers such as the AMPK agonist metformin should produce metabolic synthetic lethality in a glucose-starved cell culture milieu imitating the adverse tumor growth conditions in vivo. Under standard high-glucose conditions, metformin supplementation mostly caused cell cycle arrest without signs of apoptotic cell death. Under glucose withdrawal stress, metformin supplementation circumvented the ability of oncogenes (e.g., HER2) to protect breast cancer cells from glucose-deprivation apoptosis. Significantly, representative cell models of breast cancer heterogeneity underwent massive apoptosis (by >90% in some cases) when glucose-starved cell cultures were supplemented with metformin. Our current findings may uncover crucial issues regarding the cell-autonomous metformin's anti-cancer actions: (1) The offently claimed clinically irrelevant, non-physiological concentrations needed to observe the metformin's anti-cancer effects in vitro merely underlie the artifactual interference of erroneous glucose-rich experimental conditions that poorly reflect glucose-starved in vivo conditions; (2) the preferential killing of cancer stem cells (CSC) by metformin may simply expose the best-case scenario for its synthetically lethal activity because an increased dependency on Warburg-like aerobic glycolysis (hyperglycolytic phenotype) is critical to sustain CSC stemness and immortality; (3) the microenvironment-mediated contextual synthetic lethality of metformin should be expected to enormously potentiate the anti-cancer effect of anti-angiogenesis agents that promote severe oxygen and glucose deprivation in certain areas of the tumor tissues.
    Cell cycle (Georgetown, Tex.) 08/2012; 11(15):2782-92. · 5.36 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

anti-diabetic drug metformin
 
cancer incidence
 
challenges
 
clinical studies
 
Epidemiological studies
 
glucose uptake
 
hepatic gluconeogenesis
 
insulin levels
 
insulin resistance
 
insulin resistance syndromes
 
metformin
 
metformin use
 
numerous preclinical
 
preclinical evidence
 
skeletal muscle
 
summarise
 
therapeutic benefit
 
translating preclinical results
 
tumour growth
 
type 2 diabetes