@article{Ghassan S. Dbaibo_Youmna Kfoury_Nadine Darwiche_Shoghag Panjarian_Lina Kozhaya_Rihab Nasr_Mazen Abdallah_Olivier Hermine_Marwan El-Sabban_Hugues de Thé_Ali Bazarbachi_2007, place={Pavia, Italy}, title={Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity}, volume={92}, url={https://haematologica.org/article/view/4468}, DOI={10.3324/haematol.10968}, abstractNote={<strong>Background and Objectives</strong> Arsenic trioxide (ATO) is an effective treatment for acute promyelocytic leukemia (APL) and potentially for human T-cell leukemia virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATL). Many cytotoxic drugs induce apoptosis through the generation and accumulation of the sphingolipid breakdown product, ceramide, a coordinator of the cellular response to stress. We, therefore, investigated the contribution of ceramide to the mechanism of action of ATO in APL and ATL.<strong>Design and Methods</strong> A human APL-derived cell line (NB4), various ATL-derived lines and an HTLV-I-negative malignant T-cell line were cultured and treated with ATO. Growth and apoptosis assays were conducted. Measurements were made of ceramide, diacylglycerol, sphingomyelinase activity, sphingomyelin mass, glucosylceramide synthase activity and the <em>de novo</em> ceramide synthesis.<strong>Results</strong> Treatment of APL and ATL-derived cells with a clinically achievable concentration of ATO induced accumulation of cytotoxic levels of ceramide. The effects of ATO on ceramide levels in APL cells were more potent than those of all-<em>trans</em> retinoic acid (ATRA). ATO downregulated neutral sphingomyelinase activity. In contrast to the effect of ATRA, ATO-induced ceramide accumulation was not due to induction of acidic sphingomyelinase, but rather resulted from both <em>de novo</em> ceramide synthesis and inhibition of glucosylceramide synthase activity. Interestingly, the effects of ATO on <em>de novo</em> ceramide synthesis were similar in APL and ATL-derived cells despite the defective pathway in ATL cells.<strong>Interpretation and Conclusions</strong&gt; These results indicate that ATO-induced ceramide accumulation may represent a general mediator of the effects of ATO, which paves the way for new therapeutic interventions that target the metabolic pathway of this important sphingolipid secondary messenger.}, number={6}, journal={Haematologica}, author={Ghassan S. Dbaibo and Youmna Kfoury and Nadine Darwiche and Shoghag Panjarian and Lina Kozhaya and Rihab Nasr and Mazen Abdallah and Olivier Hermine and Marwan El-Sabban and Hugues de Thé and Ali Bazarbachi}, year={2007}, month={Jun.}, pages={753-762} }