Dicloroacetato en cancer

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British Journal of Cancer (2008) 99, 989 – 994 & 2008 Cancer Research UK All rights reserved 0007 – 0920/08 $32.00

www.bjcancer.com

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Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer


ED Michelakis*,1, L Webster1 and JR Mackey2
1

Department of Medicine, University ofAlberta, Edmonton, Canada; 2Department of Oncology, University of Alberta, Edmonton, Canada

The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the commondenominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressedmitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials. British Journal of Cancer (2008) 99, 989 – 994. doi:10.1038/sj.bjc.6604554 www.bjcancer.com Published online 2 September 2008 & 2008 CancerResearch UK
Keywords: mitochondria; metabolism; apoptosis; potassium channels; positron emission tomography; glycolysis

A PARADIGM SHIFT IS NEEDED IN CANCER THERAPEUTICS
Although some battles have been won since the declaration of the ‘war on cancer’ in 1971 in the United States, the war is ongoing. Despite enormous investments from industry and the public, oncology has an impressively poorsuccess rate in the clinical development of effective investigational drugs; less than a third of that in cardiovascular or infectious diseases (Kamb et al, 2007). Drug development in oncology has typically focused on targets essential for the survival of all dividing cells, leading to narrow therapeutic windows. Non-essential targets offer more selectivity but little efficacy. It is extremely rareto find an essential target that is unique to cancer cells; the dependence of CML cells on Ableson kinase is only induced by a chromosomal translocation in the malignant clone, making the efficacy and selectivity of imatinib for CML an exception in cancer therapy (Kamb et al, 2007). The most important reason for the poor performance of cancer drugs is the remarkable heterogeneity and adaptabilityof cancer cells. The molecular characteristics of histologically identical cancers are often dissimilar and molecular heterogeneity frequently exists within a single tumour. The view that ‘there are many different types of cancers’ is increasingly shared by scientists and clinical oncologists. This has important implications, including the realisation that specific drugs have to be developed andtested for molecularly defined tumours and effects in one might not necessarily be relevant to another cancer.

*Correspondence: Dr ED Michelakis, Department of Medicine, University of Alberta Hospital, 8440-112 Street, Edmonton, AB, Canada T6G 2B7; E-mail: evangelos.michelakis@capitalhealth.ca Received 18 December 2007; revised 28 April 2008; accepted 4 July 2008; published online 2 September2008

The biggest challenge remains the selective induction of cell death (mainly apoptosis) in cancer but not normal cells. Pragmatically, an ideal anticancer therapy would be easily administered (possibly an orally available small molecule) and affordable. Most new anticancer drugs are prohibitively expensive not only for millions of patients from developing countries, but also for many...
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