期刊
PROSTATE
卷 71, 期 10, 页码 1064-1073出版社
WILEY
DOI: 10.1002/pros.21321
关键词
ceramide; synthetic retinoids; ceramidase; cancer; chemotherapy
资金
- National Institutes of Health [GM077391, CA143755]
- Associates for Breast and Prostate Cancer Studies (Los Angeles, CA)
- Henry L. Guenther Foundation (Los Angeles, CA)
- Spanish Ministry of Science [SAF2008-00706]
- Generalitat de Catalunya [2009SGR-1072]
BACKGROUND. The purpose of this study was to determine whether the therapeutic efficacy of fenretinide (4-HPR), a ceramide-generating anticancer agent, could be enhanced in prostate cancer cells by inclusion of a novel synthetic acid ceramidase (AC) inhibitor, DM102, a pivaloylamide of a 2-substituted aminoethanol. In prostate cancer, AC plays a role in progression and resistance to chemotherapy. METHODS. PC-3 and DU 145 hormone-refractory human prostate cancer cell lines were used. Cells were exposed to 4-HPR, DM102, and combinations; viability, apoptosis, cell migration, ceramide metabolism, and levels of reactive oxygen species (ROS) were assessed. RESULTS. Single agent 4-HPR and DM102 (2.5-10 mu M) were weakly cytotoxic; however, combinations synergistically decreased cell viably to as low as 1.5% of control. N-oleoylethanolamine (NOE), a frequently employed AC inhibitor, was not effective in producing synergy. The 4-HPR/DM102 regimen enhanced caspase activity and increased [H-3](dihydro)ceramide and ROS levels 6- and 30-fold over control, respectively. The antioxidant vitamin E, but not the de novo ceramide synthesis inhibitor myriocin, partially rescued cells from 4-HPR/DM102 cytotoxicity. The 4-HPR/DM102 combination also elicited synergistic cytotoxicity in DU 145 cells, another human hormone-refractory prostate cancer cell line. CONCLUSION. This study shows that 4-HPR cytotoxicity is enhanced in a synergistic fashion by inclusion of the AC inhibitor DM102, by a mechanism that enlists generation of ROS, and thus provides a system to raise 4-HPR therapeutic potential. The role of ceramide however in the cytotoxic response is not clear, as blocking ceramide generation failed to rescue PC-3 cells from 4-HPR/DM102 cytotoxicity. Prostate 71: 1064-1073, 2011. (C) 2010 Wiley-Liss, Inc.
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