Format

Send to

Choose Destination
Prostate. 2011 Jul;71(10):1064-73. doi: 10.1002/pros.21321. Epub 2010 Dec 28.

Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide.

Author information

1
John Wayne Cancer Institute, Santa Monica, California 90404, USA.

Abstract

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 µM) 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 [(3) H](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.

PMID:
21557271
DOI:
10.1002/pros.21321
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center