Arsenic Trioxide Represses NF‐κB Activation and Increases Apoptosis in ATRA‐Treated APL Cells

Abstract 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.