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Targeting VDAC-bound hexokinase II: a promising approach for concomitant anti-cancer therapy

Introduction: Enhancement of glucose metabolism and repression of oxidative phosphorylation followed by the Warburg effect is the common hallmark of cancer cells. Hexokinase II (HKII) plays a dual role – first, HKII up-regulation results in increased glycolysis rates. Second, association of VDAC and HKII contributes to inhibition of apoptosis through repression of the formation of mitochondrial permeability transition pores. Areas covered: In this review, the role of HKII in evasion of apoptosis, aspects of HKII expression regulation, novel approaches targeting HKII and VDAC–HKII complexes and their application areas are discussed. Expert opinion: The dual role of HKII in cancer cells makes it an attractive target for anti-cancer therapy. Several agents, either synthetic or plant-derived, that target hexokinase and induce VDAC–HK complex dissociation have been identified to date. Targeting hexokinase, HK–VDAC complexes as well as other glycolytic proteins not only improves the efficacy of commonly used drugs. The most prominent benefit of this approach is the ability to overcome drug resistance, for example, to cisplatin or sorafenib. In some cases, it could create an insurmountable challenge for selection of appropriate therapy. Future studies and trials should address the issue of how to transfer these approaches into clinical practice.