Spontaneous overexpression of the long form of the bcl-X protein in a highly resistant P388 leukaemia

被引:24
作者
Kuhl, JS
Krajewski, S
Duran, GE
Reed, JC
Sikic, BI
机构
[1] STANFORD UNIV,SCH MED,DEPT MED,DIV ONCOL,STANFORD,CA 94305
[2] STANFORD UNIV,SCH MED,DEPT MED,DIV CLIN PHARMACOL,STANFORD,CA 94305
[3] BURNHAM INST,LA JOLLA,CA 92037
关键词
multidrug resistance; doxorubicin; apoptosis; murine leukaemia; bcl-X;
D O I
10.1038/bjc.1997.44
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
A novel resistant variant of murine P388 leukaemia, P388/SPR, was identified by de novo resistance to doxorubicin (DOX) in vivo. This mutant displayed a similar level of cross-resistance to etoposide (VP-16) and other topoisomerase II (topo II) inhibitors. Further analysis of the phenotype revealed a broad cross-resistance to vinca alkaloids, alkylating agents, antimetabolites, aphidicolin and UV light. Low-level expression or mdr1 and P-glycoprotein (P-gp), as well as a modest impairment of cellular drug accumulation and partial reversion of resistance to DOX and VP-16 by cyclosporine, confirmed a moderate role of P-gp in conferring drug resistance in P388/SPR cells. Consistent changes in neither topo II expression or activity nor glutathione metabolism could be detected. Induction of apoptosis was significantly reduced in P388/SPR cells, as indicated by minimal DNA fragmentation. Analysis of oncogenes regulating apoptotic cell death revealed a marked decrease of bcl-2 in combination with a moderate reduction of bax protein, but a striking overexpression of the long form of the bcl-X protein. Transfection of human bcl-X-L into P388 cells conferred drug resistance similar to that of P388/SPR cells. The data suggest that overexpression of bcl-X-L results in an unusual phenotype with broad cross-resistance to non-MDR-related cytotoxins in vitro, and provide an interesting example of spontaneous overexpression of another member of the bcl-2 gene family in cancer.
引用
收藏
页码:268 / 274
页数:7
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