Metformin is synthetically lethal with glucose withdrawal in cancer cells

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.

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1Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.


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.

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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]

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Drug that helps addicts may help treat cancer too, say experts

June 27, 2016
University of St George’s London
The drug naltrexone (LDN), which is used to treat addicts, can have a beneficial impact on cancer patients if it is given in low doses, new research suggests. 
Scientists at St George’s, University of London, say the drug naltrexone (LDN), which is used to treat addicts, can have a beneficial impact on cancer patients if it is given in low doses.
Researchers discovered that not only does LDN cause cancer cells to stop growing, it also alters their internal machinery, making them more likely to kill themselves. This can lead to other treatments becoming more effective.
The research team, led by Dr Wai Liu and Professor Angus Dalgleish and working with the company LDN Pharma, discovered that the drug, when used in these small doses, can alter the genes that regulate how a cancer cell behaves. LDN can reactivate genes that promote cell killing, as well as modify the genes that interact with the immune system to make it more unfriendly to cancer.
Dr Liu said: “We have shown that the genetic fingerprint of naltrexone differs according to the different doses used, which identifies new ways of using it as an anti-cancer treatment.
“Rather than stopping the cancer cells from growing, patients want to be rid of them. We saw that by giving the drug for two days, then withdrawing it, cancer cells would stop cycling and undergo cell death.”
Dr Liu, who has spent 20 years researching cancer treatment, hopes his research will prompt clinical trials for the use of LDN on cancer patients. He foresees LDN being used in conjunction with other cancer treatments.
At present naltrexone is licensed in many countries for the treatment of alcohol and heroin addiction, but the doses used is much higher than in this study.
However, it isn’t licensed for the treatment of other illnesses, and patients are obtaining it ‘off label’ to treat conditions such as multiple sclerosis and fibromyalgia.
Dr Liu added: “We have taken a drug that is relatively safe in humans, and reformulated a new use for it; this has only been possible by understanding the dynamics of a drug. How many other drugs can be improved in this way?
“We have shown a similar ‘repackaging’ benefit with the antimalarial drug artesunate and the cannabinoids. In both cases, drugs that are not classically cancer therapies are being trialled as such.
“This helps clinicians to devise new ways to tackle a disease that affects so many.”
The research has been published in the International Journal of Oncology.

Story Source:
The above post is reprinted from materials provided by University of St George’s LondonNote: Materials may be edited for content and length.

Journal Reference:
  1. Wai Liu, Katherine Scott, Jayne Dennis, Elwira Kaminska, Alan Levett, Angus Dalgleish. Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapyInternational Journal of Oncology, 2016; DOI: 10.3892/ijo.2016.3567