Koike K, Abe T, Hisano T, Kubo T, Wada M, Kohno K, Kuwano M
Department of Biochemistry, Kyushu University School of Medicine, Fukuoka.
Jpn J Cancer Res. 1996 Jul;87(7):765-72. doi: 10.1111/j.1349-7006.1996.tb00290.x.
Overexpression of either the multidrug resistance 1 (MDR1) gene or multidrug resistance protein (MRP) gene is involved in acquisition of multidrug-resistant phenotypes in human cancer cells. In this study we examined whether selection for resistance to the epipodophyllotoxins, etoposide/teniposide (VP16/VM26), could induce overexpression of MDR1 or MRP. We have previously isolated two VP16/VM26-resistant KB cell lines. Two VP16/VM26-resistant KB cell lines, KB/VM-1 and KB/ VM-4, which were selected by stepwise exposure to VM26 had decreased accumulation of [3H]VP16 and increased levels of MRP, but no apparent expression of MDR1 gene was observed. Another VP16/VM26-resistant KB cell line, KB/VP-4, which was further isolated from a VP16-resistant KB cell line, KB/VP-2, had decreased accumulation of [3H]VP16 and showed overexpression of MRP gene, but not that of MDR1 gene. We also isolated a VP16-resistant cell line, IN157/VP-1, from a human glioma cell line IN157. IN157/VP-1 cells showed decreased accumulation of [3H]VP16 and overexpression of MRP gene, but not of MDR1. These findings suggest that selection for resistance to VP16/VM26, preferentially induces overexpression of MRP gene.
多药耐药1(MDR1)基因或多药耐药蛋白(MRP)基因的过表达与人类癌细胞多药耐药表型的获得有关。在本研究中,我们检测了对表鬼臼毒素、依托泊苷/替尼泊苷(VP16/VM26)的耐药性选择是否能诱导MDR1或MRP的过表达。我们之前分离出了两个对VP16/VM26耐药的KB细胞系。通过逐步暴露于VM26筛选出的两个对VP16/VM26耐药的KB细胞系,KB/VM-1和KB/VM-4,其[3H]VP16的蓄积减少,MRP水平升高,但未观察到MDR1基因的明显表达。另一个对VP16/VM26耐药的KB细胞系,KB/VP-4,是从对VP16耐药的KB细胞系KB/VP-2中进一步分离得到的,其[3H]VP16的蓄积减少,显示出MRP基因的过表达,但未显示MDR1基因的过表达。我们还从人胶质瘤细胞系IN157中分离出了一个对VP16耐药的细胞系,IN157/VP-1。IN157/VP-1细胞显示[3H]VP16的蓄积减少,MRP基因过表达,但MDR基因未过表达。这些发现表明,对VP16/VM26的耐药性选择优先诱导MRP基因的过表达。