Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells
Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells
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DOI：
10.1038/sj.leu.2402104
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发表时间：
2001-05-01
期刊：
影响因子：
11.4
通讯作者：
Bhalla, KN
中科院分区：
文献类型：
--
作者：
Porosnicu, M;Nimmanapalli, R;Bhalla, KN
STI-571通过抑制Bcr-Abl的酪氨酸激酶（TK）活性，诱导HL-60/Bcr-Abl（异位表达p185 Bcr-Abl）和K562（内源性表达p210 Bcr-Abl）的分化和凋亡，而对对照HL-60细胞无诱导作用。三氧化二砷（As2O3）可降低Bcr-Abl蛋白水平并诱导Bcr-Abl阳性白血病细胞凋亡（Blood 2000; 95: 1014）。在这里，我们证明与STI-571 （0.25 ~ 1.0 muM）或As2O3 （0.5 ~ 2.0 muM）单独处理相比，As2O3和STI-571联合处理显著增加了HL60/Bcr-Abl和K562细胞的凋亡，而不是HL-60/neo细胞（P < 0.05）。As2O3和STI-571联合处理还能显著降低Bcl-x(L)、XIAP和Akt水平，抑制Akt激酶活性。用As2O3处理go可以抑制sti -571诱导的血红蛋白，这与参与红细胞分化的GATA-1转录因子的切割和下调有关。这些数据表明，将降低Bcr-Abl水平的药物（如As2O3）与抑制Bcr-Abl TK活性的药物（如STI-571）相结合的治疗策略可以有效地诱导Bcr-Abl阳性的人白血病细胞凋亡和分化。
By inhibiting the tyrosine kinase (TK) activity of Bcr-Abl, STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p185 Bcr-Abl) and K562 (containing endogenous expression of p210 Bcr-Abl) but not of the control HL-60 cells. Treatment with arsenic trioxide (As2O3) lowers Bcr-Abl protein levels and induces apoptosis of the Bcr-Abl-positive leukemic blasts (Blood 2000; 95: 1014). Here, we demonstrate that compared to treatment with STI-571 (0.25 to 1.0 muM) or As2O3 (0.5 to 2.0 muM) alone, combined treatment with As2O3 and STI-571 induced significantly more apoptosis of HL60/Bcr-Abl and K562 but not HL-60/neo cells (P < 0.05). Combined treatment with As2O3 and STI-571 also resulted in greater reductions in the levels of Bcl-x(L), XIAP and Akt, and inhibition of Akt kinase activity. Go-treatment with As2O3 inhibited STI-571-induced hemoglobin, which was associated with the cleavage and downregulation of GATA-1 transcription factor involved in erythroid differentiation. These data demonstrate that a treatment strategy which combines an agent that lowers Bcr-Abl levels, eg As2O3, with an agent that inhibits Bcr-Abl TK activity, eg STI-571, can potently induce apoptosis and differentiation of Bcr-Abl-positive human leukemic cells.