Emerging anti-cancer targets in mitochondria

Abstract

Metabolic cancer therapy should target the most aggressive and malignant tumour cells within solid tumours. Targeting of mitochondrial isocitrate dehydrogenase-2 (IDH2) by inhibitors or silencing elements would eliminate tumour cells surviving the harsh conditions of hypoxia and intermittent aglycemia as well as in progressive stages of malignancies with mutant IDH2 or IDH1, producing the oncometabolite D-2-hydroxyglutarate. Strategies for its withdrawal should also be exploited. Also, cancer-specific mitochondria-located enzymes participating in aerobic glycolysis are suitable targets of anti-cancer strategies, such as inhibition of hexokinase-2 by the small molecule 3-bromopyruvate or by post-transcriptional repression of hexokinase-2 by microRNA-143. Similarly, dichloroacetate (DCA) has been considered as a potential cancer therapeutic agent, being an efficient inhibitor of four isoforms of pyruvate dehydrogenase kinases (PDK), which by phosphorylating the E1 subunit inhibit pyruvate dehydrogenase and channel pyruvate to lactate. This, in turn, establishes the glycolytic phenotype of cancer cells. Other targets include for example the inhibitor protein of the mitochondrial ATP synthase and the facilitator of its degradation, the immediate-response factor 1 (IEX1), for which strategies dependent on the specific conditions should be exploited. However, there has been a limited number of clinical studies documenting the significance of mitochondrial targeting in cancer therapies.