Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein
Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein
复制标题
DOI：
10.1038/sj.leu.2402222
复制
发表时间：
2001-09-01
期刊：
影响因子：
11.4
通讯作者：
Oliver, L
中科院分区：
文献类型：
--
作者：
Campone, M;Vavasseur, F;Oliver, L
多药耐药（MDR）蛋白的出现或有缺陷的凋亡程序的获得是癌症治疗中的主要缺点，因为两者都诱导对经典化疗的抗性。然而，这两个机制之间的联系尚未明确确立。在这项研究中，HL-60细胞培养在亚致死剂量的阿霉素（dox; HL-60/Dox）的持续存在下被用作模型来研究获得性耐药性。在诱导化疗耐药性期间，除了抗凋亡Bcl-2、Bcl-XL和促凋亡Bax蛋白的表达之外，还评估了功能性P-糖蛋白（P-gp）的出现。亲代细胞对dox敏感，无P-gp活性，表达Scl-2和Bax。在HL-60/Dox细胞中检测到功能性P-gp。此外，Bcl-2的合成似乎被Bcl-XL取代，而Bax的合成保持不变。这些细胞也对P-gp和非P-gp底物诱导的凋亡具有抗性。这种不能诱导凋亡可能是由于诱导了凋亡抑制蛋白（XIAP）的表达。我们的数据表明，获得性耐药可能涉及一个平行的诱导P-gp和损伤的凋亡途径。
The appearance of multidrug-resistant (MDR) proteins or the acquisition of a defective apoptotic programme are major drawbacks in the treatment of cancers since both induce a resistance to classical chemotherapy. However, a link between the two mechanisms has not, as yet, been clearly established. In this study, HL-60 cells cultured in the continual presence of a sub-lethal dose of doxorubicin (dox; HL-60/Dox) were used as a model to study acquired chemoresistance. During the induction of chemoresistance, the appearance of a functional P-glycoprotein (P-gp), in addition to the expression of anti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax proteins was assessed. Parental cells which are sensitive to dox, have no P-gp activity and express Scl-2 and Bax. After 4 weeks of treatment, a functional P-gp was detected in HL-60/Dox cells. In addition, the synthesis of Bcl-2 appeared to be replaced by Bcl-XL while that of Bax remained unchanged. These cells were also resistant to apoptosis induced by both P-gp and non-P-gp substrates. This inability to induce apoptosis could have resulted from the induction of the expression of the inhibitor of apoptosis protein (XIAP). Our data show that acquired chemoresistance could involve a parallel induction of P-gp and an impairment of the apoptotic pathway.