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

Abstract

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.

• Authors: Kyeong-Hee Choi, Hyung-Kook Kim, Jun-Hee Kim, Eun-Sun Choi, Ji-Ae Shin, Syng-Ook Lee, Sudhakar Chintharlapalli, Stephen Safe, Maen Abdelrahim, Gu Kong, Hong Seok Choi, Ji-Youn Jung, Hyun-Tae Cho, Nam-Pyo Cho, Sung-Dae Cho
• Journal: European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) (Eur J Cancer Prev) Vol. 19 Issue 2 Pg. 153-9 (Mar 2010) ISSN: 1473-5709 [Electronic] England
• PMID: 19949342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5,5'-dibromo-1,1-bis(3'-indolyl)methane
• Indoles
• Proto-Oncogene Proteins c-bcl-2
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Squamous Cell (metabolism, pathology, prevention & control)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Humans
• Indoles (toxicity)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mouth Neoplasms (metabolism, pathology, prevention & control)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• p38 Mitogen-Activated Protein Kinases (metabolism)