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.