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.
OBJECTIVE
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.


METHODS
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 de novo ceramide synthesis.


RESULTS
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-trans 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 de novo ceramide synthesis and inhibition of glucosylceramide synthase activity. Interestingly, the effects of ATO on de novo ceramide synthesis were similar in APL and ATL-derived cells despite the defective pathway in ATL cells.


CONCLUSIONS
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.
Dbaibo
Ghassan S
GS
Department of Pediatrics, American University of Beirut, Beirut, Lebanon.
Kfoury
Youmna
Y
Darwiche
Nadine
N
Panjarian
Shoghag
S
Kozhaya
Lina
L
Nasr
Rihab
R
Abdallah
Mazen
M
Hermine
Olivier
O
El-Sabban
Marwan
M
de Thé
Hugues
H
Bazarbachi
Ali
A
D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*
D001152:Arsenicals; D002518:Ceramides; D010087:Oxides; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000077237:Arsenic Trioxide