Combinatory effect of 3-bromopyruvic acid and curcumin on colorectal cancer

Colorectal cancer (CRC) is the third common cancer type in both males and females in Turkey. One of the hallmarks of cancer states that cancer cells reprogram their energy metabolism, known as aerobic glycolysis, to fuel cell division and growth by producing lactate even in the presence of oxygen. Therefore, regulation of glycolysis plays a crucial role in cancer therapies. 3-bromopyruvate (3BP) causes the suppression of the glycolytic enzyme hexokinase II (HKII), results in low levels of ATP and cell death in cells. Curcumin (CUR) affects different types of cancers such as liver, skin, breast, kidney, hepatocellular carcinoma, and colorectal through apoptotic cell death. In this study, we aimed to reveal the effects of 3BP and CUR combination treatment (COT) on cellular, glycolytic, and mitochondrial metabolism in HCT116, colorectal cancer cell line. First, we revealed COT inhibits cell proliferation by 32 percent compared to each treatment alone. Cell death mechanism analysis showed that COT doubled late apoptotic cell number. The analysis with 2',7'–dichlorofluorescein diacetate fluorogenic dye to measure the generation of reactive oxygen species increased upon COT by 90 percent. Then, mitochondrial membrane potential by Rhodamine 123 dye and mitochondrial mass by Mitotracker Green FM dye were analyzed which was found as decreased by COT treatment to 35 and 36 percent, respectively. Also, alterations in protein expressions of mitochondrial OXPHOS complexes were determined by immunoblotting which revealed that Complex III (cytochrome bc1) and Complex II (succinate dehydrogenase) protein expression levels were decreased by 21 and 32 percent. Lastly, glycolytic metabolism was investigated by analyzing LDH-A protein expressions by immunoblotting which was decreased LDH-A levels to 36 percent upon COT. According to the obtained results, 3BP and CUR combination might be a potential therapeutic agent for colorectal cancer by limiting both glycolysis and OXPHOS bioenergetic pathways.