Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines
Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines
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DOI：
10.1182/blood.v93.5.1658
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发表时间：
1999-03-01
期刊：
影响因子：
20.3
通讯作者：
Dalton, WS
中科院分区：
文献类型：
--
作者：
Damiano, JS;Cress, AE;Dalton, WS
整合素介导的粘附影响细胞存活并可防止程序性细胞死亡。对药物敏感的肿瘤细胞系如何在最初暴露于细胞毒性药物后存活并最终选择耐药群体知之甚少。允许急性细胞毒性药物暴露后细胞存活的因素可能与慢性药物暴露选择的耐药机制不同。我们在此表明，药物敏感的8226人骨髓瘤细胞，被证明表达VLA-4（α（4）β（1））和VLA-5（α（5）β（1））整合素纤连蛋白（FN）受体，当预先粘附于FN并与悬浮培养的细胞相比时，对阿霉素和美法仑的凋亡作用具有相对抗性。不是由于药物蓄积减少或抗凋亡Bcl-2家族成员的上调。如通过流式细胞术所确定的，针对多柔比星或美法仑的耐药性选择的骨髓瘤细胞系过表达VLA-4。功能测定显示，与药物敏感的亲本系相比，两种耐药变体中α（4）介导的细胞粘附显著增加。当从选择压力中移除时，耐药细胞系恢复为药物敏感和α（4）-低表型。VLA-4介导的FN粘附是否比VLA-5介导的粘附具有生存优势仍有待确定，总之，我们已经证明FN介导的粘附通过抑制药物诱导的细胞凋亡而使急性暴露于细胞毒性药物的骨髓瘤细胞具有生存优势。这一发现可能解释了一些细胞如何在最初的药物暴露中存活下来，并最终表达经典的耐药机制，如MDR 1过表达。(C)1999年，美国血液学会。
Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selected for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (alpha(4)beta(1)) and VLA-5 (alpha(5)beta(1)) integrin fibronectin (FN) receptors, are relatively resistant to the apoptotic effects of doxorubicin and melphalan when pre-adhered to FN and compared with cells grown in suspension, This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulation or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with either doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in alpha(4)-mediated cell adhesion in both drug-resistant variants compared with the drug-sensitive parent line. When removed from selection pressure, drug-resistant cell lines reverted to a drug sensitive and alpha(4) -low phenotype. Whether VLA-4-mediated FN adhesion offers a survival advantage over VLA-5-mediated adhesion remains to be determined, in conclusion, we have demonstrated that FN-mediated adhesion confers a survival advantage for myeloma cells acutely exposed to cytotoxic drugs by inhibiting drug-induced apoptosis. This finding may explain how some cells survive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression. (C) 1999 by The American Society of Hematology.