Cellular responses to cancer chemopreventive agent D,L-sulforaphane in human prostate cancer cells are initiated by mitochondrial reactive oxygen species.

Abstract

PURPOSE:

Present study was undertaken to elucidate the mechanism of cellular responses to D,L-sulforaphane (SFN), a highly promising cancer chemopreventive agent.

METHODS:

Mitochondrial DNA deficient Rho-0 variants of LNCaP and PC-3 cells were generated by culture in the presence of ethidium bromide. Apoptosis was assessed by analysis of cytoplasmic histone-associated DNA fragmentation and activation of caspase-3. Immunoblotting was performed to determine the expression of apoptosis- and cell cycle-regulating proteins. Generation of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and cell cycle distribution were measured by flow cytometry.

RESULTS:

The Rho-0 variants of LNCaP and PC-3 cells were significantly more resistant to SFN-induced ROS generation, apoptotic DNA fragmentation, disruption of MMP, cytosolic release of cytochrome c, and G2/M phase cell cycle arrest compared with corresponding wild-type cells. SFN-induced autophagy, which serves to protect against apoptotic cell death in PC-3 and LNCaP cells, was also partially but markedly suppressed in Rho-0 variants compared with wild-type cells. SFN statistically significantly inhibited activities of mitochondrial respiratory chain enzymes in LNCaP and PC-3 cells.

CONCLUSION:

These results indicate, for the first time, that mitochondria-derived ROS serve to initiate diverse cellular responses to SFN exposure in human prostate cancer cells.

• Authors: Dong Xiao, Anna A Powolny, Jedrzej Antosiewicz, Eun-Ryeong Hahm, Ajay Bommareddy, Yan Zeng, Dhimant Desai, Shantu Amin, Anna Herman-Antosiewicz, Shivendra V Singh
• Journal: Pharmaceutical research (Pharm Res) Vol. 26 Issue 7 Pg. 1729-38 (Jul 2009) ISSN: 1573-904X [Electronic] United States
• PMID: 19384467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Isothiocyanates
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Sulfoxides
• Thiocyanates
• Caspase 3
• rho GTP-Binding Proteins
• sulforaphane

Topics

• Anticarcinogenic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Electron Transport (drug effects)
• Gene Deletion
• Humans
• Isothiocyanates
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, genetics, metabolism)
• Prostatic Neoplasms (drug therapy)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Sulfoxides
• Thiocyanates (pharmacology, therapeutic use)
• rho GTP-Binding Proteins (genetics, metabolism)