Abstract
Cancer remains the second most common cause of death in the US. Due to a recurrent problem with anticancer drug resistance, there is a current need for anticancer drugs with distinct modes of action for combination drug therapy We have tested two novel piperidone compounds, named 2608 (1-dichloroacetyl - 3,5-bis(3,4-difluorobenzylidene)-4-piperidone) and 2610 (1-dichloroacetyl-3,5-bis(3,4-dichlorobenzylidene)-4-piperidone), for their potential cytotoxicity on numerous human cancer cell lines. We found that both compounds were cytotoxic for breast, pancreatic, leukemia, lymphoma, colon, and fibroblast cell lines, with a cytotoxic concentration 50% (CC50) in the low micromolar to nanomolar concentration range. Further assays focused primarily on an acute lymphoblastic lymphoma and colon cancer cell lines since they were the most sensitive and resistant to the experimental piperidones. The cell death mechanism was evaluated through assays commonly used to detect the induction of apoptosis. These assays revealed that both 2608 and 2610 induced reactive oxygen species (ROS) accumulation, mitochondrial depolarization, and activated caspase-3/7. Our findings suggest that the piperidones induced cell death via the intrinsic apoptotic pathway. Additional assays revealed that both piperidones cause cell cycle alteration in lymphoma and colon cell lines. Both piperidones elicited DNA fragmentation, as evidenced by an increment in the sub-G0/G1 subpopulation in both cell lines. Similar to other related compounds, both piperidones were found to act as proteasome inhibitors by increasing the levels of poly-ubiquitinated proteins in both lymphoma and colon cell lines. Hence, the two piperidones exhibited attractive cytotoxic properties and suitable mechanisms of action, which makes them good candidates as anticancer drugs.