Fenretinide stimulates redox-sensitive ceramide production in breast cancer cells: potential role in drug-induced cytotoxicity

Abstract

The synthetic retinoid N-(4-hydroxphenyl) retinamide (4HPR) has manifold actions, which may contribute to its chemopreventive effects on breast cancer cell growth and progression. A role for ceramide as a stress-response signal is investigated here during the cytotoxic action of 4HPR in MCF-7 cells. N-(4-hydroxphenyl) retinamide induced a dose-dependent decline in cell growth and survival associated with a maximal 10-fold increase in ceramide production at 10 mM. N-(4-hydroxphenyl) retinamide exhibited a greater potency than all-trans retinoic acid (ATRA) on growth inhibition and ceramide production. The synthetic peroxisome proliferator-activated receptors agonist troglitazone (TGZ), but not the native ligand 15-deoxy-delta 12,14-prostaglandin J 2 , abrogated both these actions of 4HPR but not that of ATRA. The antioxidant N-acetylcysteine mimicked the abrogative effect of TGZ on 4HPR action, while the exogenous oxidant H 2 O 2 also stimulated ceramide production. The inhibitors of de novo ceramide synthesis, fumonisin B 1 and myriocin, blocked the ceramide response to 4HPR and partially reversed the apoptotic response, but did not prevent the overall decline in cell survival. The pancaspase inhibitor Z-VAD fmk reduced the decrease in cell survival caused by 4HPR, but did not affect the ceramide response. These findings describe a novel redox-sensitive elevation of ceramide levels associated with the cytotoxic response of breast cancer cells to 4HPR. However, a major mediatory role for this sphingolipid in this context remains equivocal.

Activation of Acid Sphingomyelinase by Protein Kinase Cδ-mediated Phosphorylation

“…For example, the chemotherapeutic agents fenretinide and anandamide were shown to induce ceramide production through activation of ASMase (36,37). However, other reports showed that ceramide generated by these agents can be blocked by fumonisin B1 treatment (38,39). In some cases, there were different results reported for the same cell line.…”

The Unhydrolyzable Fenretinide Analogue 4-Hydroxybenzylretinone Induces the Proapoptotic Genes GADD153 (CHOP) and Bcl-2–Binding Component 3 (PUMA) and Apoptosis that Is Caspase- Dependent and Independent of the Retinoic Acid Receptor

“…A role for caspase-8 and caspase-9 in 4-HPR action has also been reported (19,20). In human neuroblastoma and MCF-7 cells, pan-caspase inhibitors (BOC-d-fmk and z-VAD-fmk, respectively) were shown to significantly reduce apoptosis after 4-HPR treatment (24,44). In Fas-defective hepatoma cells, the general caspase inhibitor z-VAD-fmk completely blocked apoptosis in response to 4-HPR (20).…”

N-(4-Hydroxyphenyl)retinamide increases dihydroceramide and synergizes with dimethylsphingosine to enhance cancer cell killing

“…One mechanism whereby single agent 4-HPR has been reported to induce apoptosis and/or necrosis in cancer cells is via the increase of ceramides (21,22,30,31,40,41). However, because many studies used less precise TLC methods that could not provide in-depth structural information, it was not known which particular sphingolipid subspecies were elevated.…”