EXPRESSION OF BCL-X(L) CAN CONFER A MULTIDRUG-RESISTANCE PHENOTYPE
EXPRESSION OF BCL-X(L) CAN CONFER A MULTIDRUG-RESISTANCE PHENOTYPE
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DOI：
10.1182/blood.v86.5.1903.bloodjournal8651903
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发表时间：
1995-09-01
期刊：
影响因子：
20.3
通讯作者：
THOMPSON, CB
中科院分区：
文献类型：
--
作者：
MINN, AJ;RUDIN, CM;THOMPSON, CB
研究表明，调控凋亡性细胞死亡的基因可能在决定肿瘤细胞对化疗的敏感性方面发挥重要作用。我们最近克隆了bcl-2家族的一个成员bcl-x。为了测试bcl-x（L）表达是否影响肿瘤细胞对化疗的敏感性，我们建立了过表达bcl-x（L）的稳定细胞系，并测试了这些细胞对代谢抑制剂和化疗剂诱导的细胞死亡的抗性。Bcl-x（L）表达显著降低博莱霉素、顺铂、依托泊苷、长春新碱、潮霉素B和霉酚酸在培养物中长达4天的细胞毒性。Bcl-x（L）不阻止细胞对这些药物的反应而经历细胞周期停滞，而是阻止被处理的细胞经历凋亡。对用化疗剂博来霉素、顺铂、依托泊苷和长春新碱处理的细胞的细胞周期分析表明，药物在细胞周期内的不同位置引起生长停滞。用化疗药物处理的表达Bcl-x（L）的细胞在药物去除后保留其增殖能力。有趣的是，长春新碱处理的表达bcl-x（L）的细胞在药物去除后变成多倍体。这些数据表明，bcl-x（L）保护细胞免受各种各样的凋亡刺激，在细胞周期内的多个位置发挥作用，并赋予多药耐药表型。bcl-x（L）阻止化疗诱导的DNA损伤和细胞周期停滞引起的凋亡性细胞死亡的能力可能导致肿瘤内染色体畸变的积累。bcl-x（L）在肿瘤细胞中的表达可能是化疗疗效的重要指标。(C)1995年，美国血液学会。
It has been suggested that genes that regulate apoptotic cell death may play an important role in determining the sensitivity of tumor cells to chemotherapy. We have recently cloned a member of the bcl-2 family, bcl-x. To test whether bcl-x(L) expression affects the sensitivity of tumor cells to chemotherapy, we have created stable cell lines overexpressing bcl-x(L) and have tested these cells for resistance to cell death induced by metabolic inhibitors and chemotherapeutic agents. Bcl-x(L) expression dramatically reduces the cytotoxicity of bleomycin, cisplatin, etoposide, vincristine, hygromycin B, and mycophenolic acid for up to 4 days in culture. Bcl-x(L) does not prevent cells from undergoing cell cycle arrest in response to these drugs, but rather prevents treated cells from undergoing apoptosis. Cell-cycle analysis on cells treated with the chemotherapeutic agents bleomycin, cisplatin, etoposide, and vincristine, show that the drugs cause growth arrest in different positions within the cell cycle. Bcl-x(L), expressing cells treated with chemotherapeutic drugs retain their proliferative ability after the drugs are removed. Interestingly, vincristine-treated cells expressing bcl-x(L) become polyploid after drug removal. These data show that bcl-x(L) protects cells from a wide variety of apoptotic stimuli, acts in multiple positions within the cell cycle, and confers a multidrug resistance phenotype. The ability of bcl-x(L) to prevent apoptotic cell death in response to chemotherapy-induced DNA damage and cell-cycle arrest may contribute to the accumulation of chromosomal aberrations within tumors. The expression of bcl-x(L) in tumor cells is likely to be an important indicator of chemotherapeutic efficacy. (C) 1995 by The American Society of Hematology.