Endocrine Abstracts

Fenretinide (4-hydroxyphenyl retinamide, 4-HPR) is a synthetic retinoid that exhibits anti-neoplastic properties and clinical trials indicate a potential chemopreventative action of 4HPR in the development of ovarian cancer. Although the mechanism of 4HPR action remains largely unknown, ceramide has been recently proposed as a cellular signal.

The aim of the present study is to investigate in vitro the action of 4HPR and the retinoic acid receptor agonist all-trans-retinoic acid (ATRA) on cell growth and ceramide production in the ovarian cancer cell line A2780.

Both ATRA and 4HPR demonstrated a dose-dependent anti-proliferative effect over a 72h growth period with 4HPR exhibiting a 5-fold greater inhibition than ATRA at 5 micro mol. 4HPR also caused a dose-dependent (1-10 micro mol) increase in ceramide production after 24h as measured by enhanced incorporation of the precursor ³H palmitic acid into both C₁₈ and C₂₄ ceramide species. In contrast ATRA had no effect on cellular ceramide levels. Pre-treatment of cells with the ceramide synthase inhibitor fumonisin B1 (25 micro mol) blocked the 4HPR-induced increase in ceramide production but did not prevent the anti-proliferative action of 4HPR. The antioxidants NAC and troglitazone reduced the ceramide response to and the anti-proliferative action of 4HPR. Finally, the pan-caspase inhibitor Z-VAD-fmk also partially reduced 4HPR-induced ceramide production.

These data are consistent with a retinoid receptor-independent action of 4PHR on growth inhibition and ceramide production in A2780 ovarian cancer cells. 4HPR-induced ceramide production occurs via the de novo pathway but is not a major signal during the anti-proliferative action of 4HPR. Oxidative stress appears to partially mediate both the anti-proliferative and ceramide responses to 4HPR and caspase activation may also occur upstream of ceramide production.