Camptothecin, triptolide, and apoptosis inducer kit have differential effects on mitochondria in colorectal carcinoma cells.

Mitochondrial fission and fusion are required for cell survival, and several studies have shown an imbalance between fission and fusion in cancer. High levels of mitochondrial fusion are observed in drug-resistant tumor cells, whereas mitochondrial fission may be important in sensitizing tumor cells to chemotherapy drugs. Based on current knowledge, we hypothesized that different chemotherapeutics might differentially affect mitochondrial dynamics and energy production. Thus, we selected chemotherapeutics with different mechanisms of action (camptothecin, triptolide and apoptosis inducer kit) and investigated their effect on mitochondria in colorectal carcinoma cells. We report that these chemotherapeutics decreased the activity of complex I and reduced the mitochondrial membrane potential, and also decreased the size of mitochondria in the colorectal carcinoma cell lines DLD1 and HCT-116. Treatment with camptothecin, triptolide and/or apoptosis inducer kit results in differential effects of fission on apoptosis in these cells. Our results suggest that fission is an important process in apoptosis induced by chemotherapeutics.

Slow sulfide donor GYY4137 potentiates effect of paclitaxel on colorectal carcinoma cells.

Although paclitaxel (PTX) is potent chemotherapeutic agent commonly used in variety of cancers, in colorectal carcinoma its usage is excluded because of low effectivity. Up to now, some experimental attempts were utilized to improve sensitivity of colorectal carcinoma to PTX. We used a slow sulfide donor GYY4137 to increase sensitivity of colorectal carcinoma cells to PTX. As a model of colorectal carcinoma, we utilized three different cell lines - HCT116, SW620 and DLD1. We compared IC50 for PTX and PTX/GYY4137, cell cycle, apoptosis, ATP levels and changes in intracellular pH. We observed significant decrease in IC50 levels in PTX/GYY4137 groups compared to PTX in all three cell lines. PTX arrested cell cycle in G2/M phase. Differences in S phase were observed in HCT116 and DLD1 cells treated with 20 nM PTX/GYY4137, but not in SW620 cell. GYY4137 increased early, but not late phase of apoptosis. This increase was not detected in non-cancer EAHy926 cells. Upregulation of IP3R1 suggested involvement of these receptors in PTX and/or GYY4137 induced apoptosis. We also observed partial ATP depletion and intracellular acidification in PTX treated groups. In PTX/GYY4137 groups of all three cell lines no ATP depletion was detectable and intracellular acidification was lower than in PTX treated groups. Slight differences in all measured parameters were determined among HCT116, SW620 and DLD1 cells, which is probably due to physiological variations in these cells. Taking together, sensitivity of PTX to colorectal carcinoma cell lines could be increased by slow sulfide donor GYY4137, probably through potentiation of apoptosis.