Nimmanapalli R, Porosnicu M, Nguyen D, Worthington E, O'Bryan E, Perkins C, Bhalla K
Interdisciplinary Oncology Program, Moffitt Cancer Center, University of South Florida, Tampa 33612, USA.
Clin Cancer Res. 2001 Feb;7(2):350-7.
Bcr-Abl tyrosine kinase inhibitor STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p190 Bcr-Abl) and K562 (with endogenous expression of p210 Bcr-Abl) cells (Blood, 96: 2246-2253, 2000). Cotreatment with STI-571 partially overcomes the resistance to antileukemic drug-induced apoptosis of HL-60/Bcr-Abl and K562 cells. Tumor necrosis factor (TNF) alpha-related apoptosis-inducing ligand (Apo-2L/TRAIL), after binding with its signaling death receptors (DR4 and DR5), triggers the intrinsic "mitochondrial" pathway of apoptosis more efficiently in the cancer than do normal cells. In the present studies, we compared the apoptotic effects of Apo-2L/TRAIL, with or without cotreatment with STI-571, in HL-60/neo, HL-60/Bcr-Abl, and K562 cells. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells are relatively resistant to Apo-2L/TRAIL-induced apoptosis. In HL-60/Bcr-Abl and K562 versus HL-60/neo cells, Apo-2L/TRAIL caused less cytosolic accumulation of cytochrome c and the processing of caspase-9 and -3. This was also associated with decreased processing of caspase-8, c-FLIP(L) and Bid. Reduced effects of Apo-2L/TRAIL in Bcr-Abl-positive leukemic cells were not attributable to diminished expression of DR4 and DR5, or higher expressions of the decoy receptors DcR1 and -2 or c-FLIP(L). Cotreatment with STI-571 significantly enhanced Apo-2L/TRAIL-induced apoptosis (P < 0.01) as well as increased the processing of caspase-9 and -3 and XIAP, without affecting the levels of DR4, DR5, decoy receptors, or c-FLIP(L). Cotreatment with STI-571 did not enhance Apo-2L/TRAIL-induced apoptosis of HL-60/neo cells. These studies suggest that a combined treatment with STI-571 may be an effective strategy to selectively sensitize Bcr-Abl-positive leukemic blasts to Apo-2L/TRAIL-induced apoptosis.
Bcr-Abl酪氨酸激酶抑制剂STI-571可诱导HL-60/Bcr-Abl（异位表达p190 Bcr-Abl）和K562（内源性表达p210 Bcr-Abl）细胞分化和凋亡（《血液》，96: 2246 - 2253，2000）。STI-571联合治疗可部分克服HL-60/Bcr-Abl和K562细胞对抗白血病药物诱导凋亡的耐药性。肿瘤坏死因子（TNF）α相关凋亡诱导配体（Apo-2L/TRAIL）与其信号死亡受体（DR4和DR5）结合后，在癌症细胞中比在正常细胞中更有效地触发内在的“线粒体”凋亡途径。在本研究中，我们比较了Apo-2L/TRAIL单独或与STI-571联合治疗对HL-60/neo、HL-60/Bcr-Abl和K562细胞的凋亡作用。与HL-60/neo相比，HL-60/Bcr-Abl和K562细胞对Apo-2L/TRAIL诱导的凋亡相对耐药。在HL-60/Bcr-Abl和K562细胞与HL-60/neo细胞中，Apo-2L/TRAIL导致细胞色素c的胞质积累以及caspase-9和-3的加工减少。这也与caspase-8、c-FLIP(L)和Bid的加工减少有关。Apo-2L/TRAIL在Bcr-Abl阳性白血病细胞中的作用减弱并非归因于DR4和DR5表达减少，或诱饵受体DcR1和-2或c-FLIP(L)表达升高。STI-571联合治疗显著增强了Apo-2L/TRAIL诱导的凋亡（P < 0.01），同时增加了caspase-9和-3以及XIAP的加工，而不影响DR4、DR5、诱饵受体或c-FLIP(L)的水平。STI-571联合治疗未增强Apo-2L/TRAIL对HL-60/neo细胞的凋亡作用。这些研究表明，STI-571联合治疗可能是一种有效的策略，可使Bcr-Abl阳性白血病原始细胞对Apo-2L/TRAIL诱导的凋亡敏感。
