1. ¹Department of Biochemistry, American University of Beirut, Beirut, Lebanon
2. ²Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
3. ³Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon
4. ⁴UMR 7151 CNRS, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Paris, France

Correspondence: Dr A Habib, Department of Biochemistry, American University of Beirut, PO Box 11-0236, Beirut 113-6044, Lebanon. E-mail: ah31@aub.edu.lb; Dr A Bazarbachi, Department of Internal Medicine, American University of Beirut, PO Box 113-6044, Beirut, Lebanon. E-mail: bazarbac@aub.edu.lb

⁵These authors contributed equally to this work.

Received 10 January 2008; Accepted 15 February 2008; Published online 20 March 2008.

Abstract

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) triggers cell differentiation, while arsenic trioxide (As₂O₃) generates partial differentiation and apoptosis. Animal and human studies suggest that newly diagnosed APL patients can be cured using As₂O₃ combined with ATRA. Cyclooxygenases are involved in prostaglandins and thromboxane synthesis. We have recently demonstrated that ATRA induces cyclooxygenase-1 (COX-1) expression and prostaglandin synthesis in NB4 cells and in blasts from patients with APL. In the present study we investigated the effect of ATRA and As₂O₃ co-treatment on COX-1 expression and prostaglandin formation and tested the effect of the COX-1/COX-2 nonselective inhibitor indomethacin on cell differentiation. Arsenic treatment of NB4 cells resulted in a partial but significant reduction of ATRA-dependent induction of COX-1 expression and activity. Pretreatment of NB4 cells with indomethacin significantly impaired ATRA/As₂O₃-induced differentiation, as assessed by cell morphology, nitroblue tetrazolium test or CD11c expression. PGE₂ reversed the negative effect of indomethacin on differentiation of ATRA/As₂O₃-treated NB4 cells. In conclusion, COX-1 contributes to ATRA-dependent maturation of NB4 cells and is affected by As₂O₃. These results also suggest that nonsteroidal antiinflammatory drugs should be avoided in APL patients treated with the combination of ATRA and As₂O₃.