Targeting mitochondrial bioenergetics by combination treatment with imatinib and dichloroacetate in human erythroleukemic K‑562 and colorectal HCT‑116 cancer cells

Abstract

Tumor malignant cells are characterized by dysregulation of mitochondrial bioenergetics due to the 'Warburg effect'. In the present study, this metabolic imbalance was explored as a potential target for novel cancer chemotherapy. Imatinib (IM) downregulates the expression levels of SCO2 and FRATAXIN (FXN) genes involved in the heme-dependent cytochrome c oxidase biosynthesis and assembly pathway in human erythroleukemic IM-sensitive K-562 chronic myeloid leukemia cells (K-562). In the present study, it was investigated whether the treatment of cancer cells with IM (an inhibitor of oxidative phosphorylation) separately, or together with dichloroacetate (DCA) (an inhibitor of glycolysis), can inhibit cell proliferation or cause death. Human K-562 and IM-chemoresistant K-562 chronic myeloid leukemia cells (K-562R), as well as human colorectal carcinoma cells HCT-116 (+/+p53) and (−/−p53, with double TP53 knock-in disruptions), were employed. Treatments of these cells with either IM (1 or 2 μ M) and/or DCA (4 mM) were also assessed for the levels of several process biomarkers including SCO2, FXN, lactate dehydrogenase A, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase M2, hypoxia inducing factor-1a, heme oxygenase-1, NF-κB, stem cell factor and vascular endothelial growth factor via western blot analysis. Computational network biology models were also applied to reveal the connections between the ten proteins examined. Combination treatment of IM with DCA caused extensive cell death (>75%) in K-562 and considerable (>45%) in HCT-116 (+/+p53) cultures, but less in K-562R and HCT-116 (−/−p53), with the latter deficient in full length p53 protein. Such treatment, markedly reduced reactive oxygen species levels, as measured by flow-cytometry, in K-562 cells and affected the oxidative phosphorylation and glycolytic biomarkers in all lines examined. These findings indicated, that targeting of cancer mitochondrial bioenergetics with such a combination treatment was very effective, although chemoresistance to IM in leukemia and the absence of a full length p53 in colorectal cells affected its impact.