Arsenic trioxide represses NF-kappaB activation and increases apoptosis in ATRA-treated APL cells.
Acute promyelocytic leukemia (APL) is characterized by an arrest of granulopoiesis at the promyelocytic stage. The sensitivity of APL cells to all-trans retinoic acid (ATRA)-induced differentiation has been successfully exploited for treatment of the disease. We previously reported that ATRA-induced NF-kappaB activation in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells. This prosurvival effect of NF-kappaB results from its ability to repress c-jun N terminal kinase (JNK) activation. We here report that arsenic trioxide (As2O3) can overcome the antiapoptotic effect of ATRA-induced NF-kappaB activity. As2O3 antagonizes ATRA-induced degradation of the NF-kappaB inhibitor IkappaB and consequently decreases NF-kappaB activation. Also, cotreatment of NB4 cells with ATRA and As2O3 results in a higher JNK activation than treatment with ATRA alone. Our results demonstrate a proapoptotic effect of As2O3 in ATRA-treated APL cells and suggest that As2O3 may be helpful in reducing incidence of side effects linked to accumulation of mature cells, like the ATRA syndrome.
Mathieu
Julie
J
INSERM U685, Centre Hayem, Hôpital St. Louis, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France. julie.mathieu@stlouis.inserm.fr
Besançon
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D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001483:Base Sequence; D015342:DNA Probes; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D001152:Arsenicals; D015342:DNA Probes; D016328:NF-kappa B; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide