AICAR Induces Apoptosis in Chronic Lymphocytic Leukemia Cells through the Mitochondrial Pathway and Independently of p53 Pathway and AMPK Activation.

Abstract 4819

AICAR (5-aminoimidazole-4-carboxamide riboside or acadesine) induces apoptosis in different cell types including chronic lymphocytic leukemia (CLL) cells. Here, we have analyzed the mechanisms involved in AICAR-induced apoptosis in CLL cells. AICAR induced apoptosis through the mitochondrial pathway, since inhibition of caspase-8 did not protect CLL cells from AICAR-induced apoptosis and caspase inhibition did not alter cytochrome c release induced by AICAR. AICAR induced a significant increase in the mRNA levels of the proapoptotic BH3-only genes BIM, BNIP3, BNIP3L, HRK, MOAP1, and NOXA. These changes were AICA ribotide (ZMP) accumulation-dependent and adenosine monophosphate-activated protein kinase (AMPK) activation-independent in CLL cells. Furthermore, AICAR induced the accumulation of NOXA protein in all CLL samples and BIM protein in about half of these samples, without modifying the levels of other BCL-2 family proteins analyzed. Importantly, AICAR induced apoptosis irrespective of the tumor suppressor TP53 and ataxia telangiectasia mutated status in CLL cells. AMPK activation with phenformin or A-769662 did not induce apoptosis in CLL cells. Finally, AICAR induced apoptosis in B lymphocytes from AMPKa1^−/− mice. Taken together, our results demonstrate that AICAR induces apoptosis in B lymphocytes through the mitochondrial pathway by an AMPK- and p53-independent mechanism.