Chemoprevention with the metabolism modifying drugs dichloroacetate and metformin in Trp53+/- mice

While genetic testing for familial cancer susceptibility factors has excelled in recent years, the prevention options for those carrying high risk alleles have not. Altered bioenergetics has now been acknowledged as an emerging hallmark of cancer, and is believed to be a critical characteristic acquired during tumorigenesis. Several very safe drugs are available that can modify bioenergetics. Dichloroacetate (DCA) inactivates pyruvate dehydrogenase kinase, resulting in activation of pyruvate dehydrogenase, reduced lactic acid production and increased mitochondrial activity. Metformin, a type 2 diabetes treatment which activates AMPK, thereby inhibiting mTOR, has unambiguously been demonstrated to reduce the risk of many cancer types in diabetics where insulin treatments do not. We have tested these drugs as chemopreventive agents against the mammary tumours that occur in the spontaneous BALB/c-Trp53+/- mouse tumour model.