The p38 MAPK pathway is critical for 5,5′-dibromodiindolylmethane- induced apoptosis to prevent oral squamous carcinoma cells

Cruciferous vegetables contain isothiocyanates including diindolylmethane (DIM) that exhibit cancer chemopreventive effects. We developed a series of synthetic ring-substituted DIM analogs including 5,5′-dibromoDIM that exhibited better inhibitory activity in breast and colon cancer cells than DIM. In this study, we investigated whether 5,5′-dibromoDIM inhibits the proliferation of KB and YD-10B oral squamous carcinoma cell lines. 5,5′-dibromoDIM decreased the cell survival and inhibited the growth of oral cancer cells. Exposure of KB and YD-10B cells to 5,5′-dibromoDIM induced caspase-dependent apoptosis evidenced by poly-ADP ribose polymerase cleavage, accumulation of sub-G1 population, and nuclear condensation and fragmentation. In addition, apoptotic cell death was correlated with damage to the mitochondrial membrane potential through a decrease in the level of Bcl-2 protein expression. Mechanistic studies showed that mitochondria-dependent apoptosis induced by 5,5′-dibromoDIM was mediated by the p38 mitogen-activated protein kinase pathway but not the ERK1/2 and JNK pathway. These results highlight 5,5′-dibromoDIM as an important chemopreventive agent for the clinical treatment of oral cancer through the p38 mitogen-activated protein kinase pathway.