Konopleva, Marina; Contractor, Rooha; Tsao, Twee; Samudio, Ismael; Ruvolo, Peter P; Kitada, Shinichi; Deng, Xingming; Zhai, Dayong; Shi, Yue-Xi; Sneed, Thomas; Verhaegen, Monique; Soengas, Maria; Ruvolo, Vivian R; McQueen, Teresa; Schober, Wendy D; Watt, Julie C; Jiffar, Tilahun; Ling, Xiaoyang; Marini, Frank C; Harris, David; Dietrich, Martin; Estrov, Zeev; McCubrey, James; May, W. Stratford; Reed, John C; Andreeff, Michael
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia
Teil von
  • Cancer cell, 2006, Vol.10 (5), p.375-388
Ort / Verlag
CAMBRIDGE: Elsevier Inc
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BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.
ISSN: 1535-6108
ISSN: 1878-3686
DOI: 10.1016/j.ccr.2006.10.006

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