Wilson P D, Hreniuk D, Lenard J
Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School (at Rutgers), Piscataway 08854.
Biochem Biophys Res Commun. 1991 May 15;176(3):1377-82. doi: 10.1016/0006-291x(91)90439-e.
Multidrug resistance (MDR) in cultured cells and tumors is associated with overproduction of P-glycoprotein, a plasma membrane efflux pump normally present at very low levels. The cytotoxic action of N-dodecylimidazole (C12-Im), a lysosomotropic detergent, on cultured cells was previously shown to be strongly dependent on growth state, with rapidly growing cells being most sensitive and confluent cells most resistant. We show here that this may be due to a growth dependent increase in cellular P-glycoprotein activity. Both verapamil and nifedipine, structurally unrelated P-glycoprotein inhibitors, increased markedly the sensitivity of CHO fibroblasts to killing by C12-Im; the increase was greater in confluent than in growing cells. Also, verapamil inhibitable 3H-daunomycin efflux was more efficient from confluent than from subconfluent cells. The MDR cell line CH(R)C5 differed from all cell lines previously examined in that it did not show a growth-dependent decrease in C12-Im sensitivity, and sensitivity was not increased by verapamil or nifedipine. We suggest that a growth-dependent increase in MDR activity is a general property of cultured cells, except for those specifically overexpressing P-glycoprotein.
培养细胞和肿瘤中的多药耐药性（MDR）与P-糖蛋白的过度产生有关，P-糖蛋白是一种通常以极低水平存在的质膜外排泵。溶酶体促透性去污剂N-十二烷基咪唑（C12-Im）对培养细胞的细胞毒性作用先前已表明强烈依赖于生长状态，快速生长的细胞最敏感，汇合细胞最耐药。我们在此表明，这可能是由于细胞P-糖蛋白活性的生长依赖性增加。维拉帕米和硝苯地平这两种结构不相关的P-糖蛋白抑制剂，均显著增加了CHO成纤维细胞对C12-Im杀伤的敏感性；汇合细胞中的增加幅度大于生长细胞。此外，维拉帕米可抑制的3H-柔红霉素外排在汇合细胞中比在亚汇合细胞中更有效。MDR细胞系CH(R)C5与先前检查的所有细胞系不同，它未表现出对C12-Im敏感性的生长依赖性降低，且维拉帕米或硝苯地平未增加其敏感性。我们认为，除了那些特异性过表达P-糖蛋白的细胞外，MDR活性的生长依赖性增加是培养细胞的普遍特性。
