Synergistic induction of apoptosis of neuroblastoma by fenretinide or CD437 in combination with chemotherapeutic drugs

Retinoic acid therapy improves the survival of children with neuroblastoma and 13-cis retinoic acid now forms an important component of treatment for residual disease of stage IV neuroblastoma after chemotherapy, However, alt hough 13-cis retinoic acid induces differentiation, other retinoids are eff ective at inducing apoptosis of neuroblastoma in vitro, including the novel compounds fenretinide and CD437 and these may be! alternative retinoids fo r neuroblastoma therapy. The aim of our study was to evaluate the ability o f fenretinide, CD437 (6-{3-(1-adamantyl)-4-hydroxyphenyl) -2-naphthalene ca rboxylic acid) and different retinoic acid isomers to induce apoptosis of n euroblastoma in conjunction with the chemotherapeutic drugs, cisplatin, eto poside and carboplatin. Neuroblastoma cell lines were treated with retinoid s prior to treatment with chemotherapeutic agents and flow cytometry used t o measure apoptosis and free radical generation. Pre-treatment of neuroblas toma cell lines with fenretinide or CD437 prior to treatment with cisplatin , etoposide or carboplatin synergistically increased apoptosis, an effect n ot seen with 13-cis, all trans or 9-cis retinoic acid. Contrary to retinoic acid isomers or chemotherapeutic drugs, apoptosis of neuroblastoma cells i nduced by fenretinide or CD437 was accompanied by the generation of intrace llular free radicals. Quenching of fenretinide- or CD437-induced free radic als with antioxidants abolished the synergistic response seen with the subs equent addition of chemotherapeutic agents. Therefore, the generation of fr ee radicals by fenretinide or CD437 may be the key property of these retino ids leading to synergistic responses with chemotherapeutic drugs. Clearly, these synthetic retinoids provide new opportunities for novel neuroblastoma therapy, Int. J. Cancer 88:977-985, 2000. (C) 2000 Wiley-Liss, Inc.