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p38^MAPK-Dependent Sensitivity of Ewing's Sarcoma Family of Tumors to Fenretinide-Induced Cell Death

Authors' Affiliations: ¹ Candlelighter's Children's Cancer Research Laboratory, Cancer Research UK Clinical Centre, Leeds, United Kingdom and ² Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

Requests for reprints: Susan A. Burchill, Candlelighter's Children's Cancer Research Laboratory, Cancer Research UK Clinical Centre, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom. Phone: 44-113-2065873; Fax: 44-113-2429886; E-mail: S.A.Burchill{at}leeds.ac.uk.

Purpose: There is an urgent need for new therapeutic strategies in Ewing's sarcoma family of tumors (ESFT). In this study, we have evaluated the effect of fenretinide [N-(4-hydroxyphenyl)retinamide] in ESFT models.

Experimental Design: The effect of fenretinide on viable cell number and apoptosis of ESFT cell lines and spheroids and growth of s.c. ESFT in nu/nu mice was investigated. The role of the stress-activated kinases p38^MAPK and c-Jun NH₂-terminal kinase in fenretinide-induced death was investigated by Western blot and inhibitor experiments. Accumulation of reactive oxygen species (ROS) and changes in mitochondrial transmembrane potential were investigated by flow cytometry.

Results: Fenretinide induced cell death in all ESFT cell lines examined in a dose- and time-dependent manner. ESFT cells were more sensitive to fenretinide than the neuroblastoma cell lines examined. Furthermore, fenretinide induced cell death in ESFT spheroids and delayed s.c. ESFT growth in mice. p38^MAPK was activated within 15 minutes of fenretinide treatment and was dependent on ROS accumulation. Inhibition of p38^MAPK activity partially rescued fenretinide-mediated cell death in ESFT but not in SH-SY5Y neuroblastoma cells. c-Jun NH₂-terminal kinase was activated after 4 hours and was dependent on ROS accumulation but not on activation of p38^MAPK. After 8 hours, fenretinide induced mitochondrial depolarization (_m) and release of cytochrome c into the cytoplasm in a ROS- and p38^MAPK-dependent manner.

Conclusions: These data show that the high sensitivity of ESFT cells to fenretinide is dependent in part on the rapid and sustained activation of p38^MAPK. The efficacy of fenretinide in preclinical models demands the evaluation of fenretinide as a potential therapeutic agent in ESFT.

Key Words: stress-activated kinases • retinamides • ESFT • neuroblastoma