As opposed to cytotoxic therapy, a new approach is targeting the ravenous metabolic needs of the cancers cells and therefore starving them. This does not immediately eliminate these cells but rather slow the metabolism inhibiting glucose uptake and changes or regression of the tumors occur many days or months after and eventually die (Zhao et al., 2013[AO1] ). Hence, a key for therapy is using a combination of chemotherapy enhancing cell cytotoxicity with the assistance of metabolic inhibitors and therefore attenuate the cytotoxic impact on normal cells. This therapeutic window opens for targeting metabolic enzymes and glucose transporters (GLUT) blocking the dramatic glucose reuptake, pyruvate kinase M2(PKM2) as a key enzyme regulating glycolysis and oxidative phosphorylation (Chao et al., 2017), hexokinase 2 (HK2) expressed at a higher level in cancer cells and responsible for tumor initiation and maintenance (Patra et al., 2013), pyruvate dehydrogenase kinase which catalyses the phosphorylation of the mitochondrial pyruvate dehydrogenase complex which acts as gatekeeper for energy metabolism (Saunier et al., 2016) fatty acid synthase (FASN) involved in neoplastic lipogenesis, glutaminase for glutamine to glutamate conversion used for proliferation, and finally the approach in this study being lactate dehydrogenase A (LDHA). LDHA catalyzes the reduction of pyruvate to lactate consuming NADH+ + H+ while LDHB does opposite, it oxidizes lactate to pyruvate giving NADH+ + H+ (Brisson et al., 2016). Lactate is exported while pyruvate is consumed via aerobic glycolysis (TCA cycle). Compared to normal cells which in an oxygenated environment use oxidative phosphorylation pathway for ATP production (yielding 36 ATP), cancer cells despite available oxygen do not completely shut off this pathway but is dramatically reduced to 5% and the rest of the energy is obtained from conversion of pyruvate to lactate, thus making LDHA a vital enzyme for cancer cells survival conditions (Brisson et al., 2016). This is termed “Warburg effect”, which when targeted and reversed may be a potential treatment method to combat cancer.
[AO1]You must follow the instruction! Please, cite the papers as I did for few above paragraphs. Mark the citation in yellow both in the text and references. You can make it easy by spliting the page (split the window).