Targeting HK2 in Anticancer Therapy

Abstract

Altered glucose metabolism is characteristic of many cancer cells, especially in the hypoxic zone of solid tumours, which is associated with a poor prognosis. Hexokinase (HK) is an enzyme involved in the first step of glycolysis, the phosphorylation of 6-OH in glucose molecules. Hexokinase 2 (HK2) is one of the isoforms overexpressed in cancer cells. In addition, HK2 binds to the voltage-dependent anion channel 1 (VDAC1) located on the outer mitochondrial membrane, protecting the cancer cell from apoptosis. Targeting HK2 shows promise for a novel therapy in cancer treatment. HK2 inhibitors inhibit glycolysis, reduce the energy supply to cancer cells, and disrupt the function of the HK2-VDAC1 complex, thereby inhibiting cancer growth and development. According to recent studies, the use of HK2 inhibitors together with known antitumour drugs in combined therapy improves efficacy in solid tumour treatment. This may be colligated to the susceptibility of the hypoxic cells to anaerobic glycolysis and their resistance to anticancer therapies such as chemotherapy and radiotherapy. This review describes the function and expression of HK2 in cancer cells and the differences between HK2 and other isoforms. We present systematized reported HK2 inhibitors with clinical potential in the treatment of cancer and indicate that the main limitation of HK2 inhibitors usage is low selectivity HK2 inhibitors and consequently their cytotoxicity. The present study reconfirms a strong necessity to develop new effective and selective HK2 inhibitors.