Fenretinide cytotoxicity is independent of both constitutive and pharmacologically modulated glutathione levels in pediatric acute lymphoblastic leukemia cells cultured at hypoxia

Fenretinide (4-HPR) cytotoxicity relative to glutathione levels in pediatric acute lymphoblastic leukemia cell lines cultured at bone marrow level hypoxia (5% O2) is evaluated. 4-HPR cytotoxicity correlated with reactive oxygen species generation (P < 0.001), but not with levels of intracellular glutathione, γ-glutamylcysteine synthase, or glutathione peroxidase. Buthionine sulfoximine (BSO) reduced glutathione levels in 10 cell lines (P < 0.001), but 4-HPR + BSO was markedly synergistic in only 1 of 10 lines. Pretreatment with N-acetylcysteine increased glutathione (P < 0.02) but did not alter 4-HPR cytotoxicity. Our data suggest that 4-HPR cytotoxicity is independent of glutathione under physiologic oxygen tension. Pediatr Blood Cancer 2012; 58: 994–997. © 2011 Wiley Periodicals, Inc.