Cell Cycle. 2012 Aug 1;11(15):2782-92. doi: 10.4161/cc.20948. Epub 2012 Aug 1.
Metformin is synthetically lethal with glucose withdrawal in cancer cells.
Menendez JA1, Oliveras-Ferraros C, Cufí S, Corominas-Faja B, Joven J, Martin-Castillo B, Vazquez-Martin A.
1Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain. firstname.lastname@example.org
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.
Metformin is synthetically lethal with glucose withdrawal in cancer cells. [Cell Cycle. 2012]
“Double hit” makes the difference. [Cell Cycle. 2012]
[PubMed – indexed for MEDLINE]
Mini Rev Med Chem. 2014 Aug 19. [Epub ahead of print]
Combined Cancer Therapy with Non-Conventional Drugs: all Roads Lead to AMPK.
1The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, No. 169 Changle West Road, 710032, Xi’an, PR China. email@example.com.
AMP-activated protein kinase (AMPK) is a key energy sensor that regulates cellular energy homeostasis. AMPK activation is associated with decreased phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase and causes a general reduction in mRNA translation and protein synthesis. Therefore, AMPK is a novel target for anti-cancer therapy. Metformin and aspirin are two traditional drugs that are widely used as anti-diabetes and non-steroidal anti-inflammatory drugs (NSAIDs), respectively. Much evidence has confirmed that these two drugs demonstrated encouraging anti-cancer properties. Most importantly, both inhibited tumor proliferation and were mainly dependent on the AMPK/mTOR signaling pathway. In addition, several other drugs, such as resveratrol,C, berberine, statins, epigallocatechin gallate (EGCG) and capsaicin, have provided a similar capacity for tumor inhibition, and the anti-cancer effects of most of them were mainly the result of AMPK activation. In the current review, we summarize the literature on combination therapy based on these non-classical drugs and their potential mechanisms for activating AMPK. Combinations of these drugs will provide a novel cancer therapeutic regimen.
PMID:25138094 [PubMed – as supplied by publisher]
Cancer Prev Res (Phila). 2014 Feb 11. [Epub ahead of print]
Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment.
1Medicine/Population Science, Rutgers Cancer Insititue of New Jersey.
Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3-5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMPK-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of Cox-1/Cox-2 and modulation of the NFκB or STAT3 pathway. Additionally, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer.
PMID:24520038 [PubMed – as supplied by publisher]
Cancer Lett. 2014 Jan 27. pii: S0304-3835(14)00041-X. doi: 10.1016/j.canlet.2014.01.015. [Epub ahead of print]
Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells.
Choi YW1, Lim IK2.
1Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration Project, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
2Department of Biochemistry and Molecular Biology, BK21 Cell Transformation and Restoration Project, Ajou University School of Medicine, Suwon 443-721, Republic of Korea. Electronic address: firstname.lastname@example.org.
To investigate sensitization of metformin-cytotoxicity, cancer cells were treated with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK). Metformin-cytotoxicity was mainly dependent on glucose availability and reducing power generated by pentose phosphate pathway, whereas DCA cotreatment enhanced metformin-cytotoxicity via reprogramming glucose metabolism by inhibiting PDK and increasing mitochondrial respiration. DCA cotreatment elicited cell death rather than cell survival despite high glucose and high GSH condition. In conclusion, DCA sensitized metformin-cytotoxicity by reprogramming glucose metabolism in part from aerobic glycolysis to mitochondrial oxidation, evidenced by measurements of glucose consumption, lactate release, and the ratio of oxygen consumption rate/extracellular acidification rate.
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