Combination effect of dichloroacetate and 3-bromopyruvate in colorectal cancer cell line HT-29: the mitochondrial pathway apoptosis

5-Fluorouracil (5-FU) is considered as the first line treatment for colorectal cancer, but its effectiveness is limited by drug resistance and this resistance is an important factor in treatment failure colon cancer, therefore the new combination drug for colon cancer treatment strategy is needed. The goal of cancer treatment is to prevent proliferation (cytostatic effects) and cell death (cytotoxic effects) of cancer cell. The goal of the therapies is to achieve an effective outcome with minimal side effects. Therefore, we should look for drugs with high efficacy and fewer side effects. Mitocans (Derived from mitochondrial terms and cancer), they can be considered an effective anticancer drug because of their high specificity in targeting cancer cells. In our study, we have described the apoptotic effect of mitochondria-targeted compound 3Br-P + DCA in HT-29 colorectal cancer cell line. 3Br-P as a potent inhibitor of hexokinase that suppress energy metabolism in the cancer cell and trigger cell death. Dichloroacetate (DCA) by inhibiting the pyruvate dehydrogenase kinase enzyme activates pyruvate dehydrogenase, which ultimately boosts the production of Acetyl-CoA as a precursor to the Krebs cycle, increases the activity of the Krebs’ cycle that cause accelerate activity of the electron transfer chain. In our study, combined 3Br-P and DCA significantly elevated reactive oxygen species levels and induced mitochondrial permeability transition pore, consequently release caspase 3 to cytosol that can promote Bax/Bcl-2 ratio expression which ultimately activated of mitochondria-dependent apoptosis. While cancer targeted therapies were designed to target a specific molecule that is critical for the growth and expansion of cancer cell so blocking these molecules can kill cancer cell or prevent them from growing and less harm to normal cells. Many drug groups have been approved for targetedtherapies of cancer cells, one of which induces apoptosis. According to the mitocans features we can consider them included apoptosis inducers.

Keywords:

Apoptosis , 3-Bromopyruvate , Dichloroacetate , Colorectal cancer cells , 5-Fluorouracil