Collateral sensitivity to the bisdioxopiperazine dexrazoxane (ICRF-187) in etoposide (VP-16) resistant human leukemia K562 cells
Collateral sensitivity to the bisdioxopiperazine dexrazoxane (ICRF-187) in etoposide (VP-16) resistant human leukemia K562 cells
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DOI：
10.1016/0006-2952(96)00338-3
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发表时间：
1996-08-23
影响因子：
5.8
通讯作者：
Yalowich, JC
中科院分区：
文献类型：
--
作者：
Fattman, CL;Allan, WP;Yalowich, JC
依托泊苷（VP-16）耐药K562细胞（K/VP. 5）对VP-16的耐药性为26倍，部分原因是DNA拓扑异构酶II（拓扑异构酶II）蛋白水平降低。与亲代K562细胞相比，VP-16耐药K/VP.5细胞对右雷佐生（ICRF-187）的敏感性高3.4倍，右雷佐生是一种拓扑异构酶II抑制剂，不稳定拓扑异构酶II-DNA共价复合物。相比之下，K/VP.5细胞对甲基巴龙的交叉耐药性为4.0倍，对fostriecin没有交叉耐药性，fostriecin是另外两种不稳定拓扑异构酶II-DNA共价复合物的拓扑异构酶II抑制剂。ICRF-187预孵育导致K/VP.5细胞中后续VP-16诱导的拓扑异构酶II-DNA共价复合物的抑制作用大于K562细胞。相反，与甲基巴龙预孵育导致在K/VP.5细胞中VP-16诱导的拓扑异构酶II-DNA共价复合物的抑制作用低于亲本K562细胞。与fostriecin预孵育VP-16诱导的拓扑异构酶II-DNA共价复合物的形成在任何细胞系的影响不大。在敏感细胞和耐药细胞中，ICRF-187抑制VP 16诱导的拓扑异构酶II-DNA复合物形成的发生率相似。此外，ICRF-187对K562和K/VP.5细胞的拓扑异构酶II催化活性具有相当的浓度依赖性抑制作用。总之，我们的研究结果表明，在K/VP.5细胞中对ICRF-187的附带敏感性是由于拓扑异构酶II蛋白水平降低，而不是拓扑异构酶II活性的改变。此外，结果表明，ICRF-187，甲基巴龙，和fostriecin具有不同的作用机制，可以有效地研究在K/VP.5和K562细胞。
Etoposide (VP-16)-resistant K562 cells (K/VP.5) were 26-fold resistant to VP-16, due in part to a reduction in DNA topoisomerase II (topoisomerase II) protein levels. Compared with parental K562 cells, VP-16 resistant K/VP.5 cells were found to be 3.4-fold more sensitive to the effects of dexrazoxane (ICRF-187), a topoisomerase II inhibitor that does not stabilize topoisomerase II-DNA covalent complexes. In contrast, K/VP.5 cells were 4.0-fold cross-resistant to merbarone and showed no cross-resistance to fostriecin, two other topoisomerase II inhibitors that do not stabilize topoisomerase II-DNA covalent complexes. Preincubation with ICRF-187 resulted in greater inhibition of subsequent VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in K562 cells. Conversely, preincubation with merbarone resulted in less inhibition of VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in parental K562 cells. Preincubation with fostriecin had little effect on VP-16-induced topoisomerase II-DNA covalent complex formation in either cell line. The onset rates for ICRF-187 inhibition of VP 16-induced topoisomerase II-DNA complex formation were similar in sensitive and resistant cells. In addition, ICRF-187 had a comparable concentration-dependent inhibitory effect on the topoisomerase II catalytic activities of K562 and K/VP.5 cells. Together, our results indicate that collateral sensitivity to ICRF-187 in K/VP.5 cells is due to decreased topoisomerase II protein levels rather than to an alteration in topoisomerase II activity. Furthermore, results suggest that ICRF-187, merbarone, and fostriecin have different mechanisms of action that can be studied effectively in K/VP.5 and K562 cells.