Mitochondria-targeting drugs arsenic trioxide and lonidamine bypass the resistance of TPA-differentiated leukemic cells to apoptosis

Exposure of U937 human leukemic cells to the phorbol ester 12-O-tetradecano yl-phorbol 13-acetate (TPA) induces their differentiation into monocyte/mac rophage-like cells. This terminal differentiation is associated with a resi stant phenotype to apoptosis induced by the topoisomerase II inhibitor etop oside, The inhibition occurs upstream of the mitochondrial release of cytoc hrome c and the activation of procaspase-2, -3, -6, -7, -8, and -9, By usin g cell-free systems, it was demonstrated that the mitochondrial pathway to cell death that involves mitochondrial membrane depolarization, cyto- chrom e c release and cytosolic activation of procaspases by cytochrome c/dATP re mains functional in TPA-differentiated U937 cells. Accordingly, 2 drugs rec ently shown to target the mitochondria, namely lonidamine and arsenic triox ide, bypass the resistance of TPA-differentiated U937 cells to classical an ticancer drugs. Cell death induced by the 2 compounds is associated with mi tochondrial membrane depolarization, release of cytochrome c and Smac/Diabl o from the mitochondria, activation of caspases, poly(ADP-ribose) polymeras e cleavage and internucleosomal DNA fragmentation. Moreover, the decreased glutathione content associated with the differentiation process amplifies t he ability of arsenic trioxide to activate the mitochondrial pathway to cel l death. Similar results were obtained by comparing undifferentiated and TP A-differentiated human HL60 leukemic cells. These data demonstrate that mit ochondria-targeting agents bypass the resistance to classical anticancer dr ugs induced by TPA-mediated leukemic cell differentiation.