The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy
The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy
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DOI：
10.1038/sj.leu.2402257
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发表时间：
2001-10-01
期刊：
影响因子：
11.4
通讯作者：
Neckers, LM
中科院分区：
文献类型：
--
作者：
Blagosklonny, MV;Fojo, T;Neckers, LM
Bcr-Abl融合蛋白驱动白血病发生，并可使白血病细胞对传统化疗产生抗药性。格尔达那霉素(GA)是一种破坏Hsp90相关蛋白稳定的药物，它会耗尽Hsp90客户BCR-Abl的细胞，但不会耗尽Abl的细胞。转导bcr-Abl的HL60细胞和自然Ph阳性的K562白血病细胞对大多数细胞毒药物都有耐药性，但对GA敏感。此外，GA还使表达bcr-Abl的细胞对阿霉素(DOX)和紫杉醇(PTX)增敏。相反，在亲代HL60细胞中，90 nm GA可抑制500 ng/mlDOX引起的PARP裂解、核碎裂和细胞死亡。与GA一样，STI571(Abl激酶的抑制剂)使表达bcr-Abl的细胞对DOX敏感。与GA不同，STI 571不能拮抗DOX对HL60细胞的细胞毒作用。这些结果表明，bcr-Abl对表达bcr-Abl的细胞的增敏作用，而不是对HL60细胞的减敏作用，依赖于对bcr-Abl的抑制。因此，GA根据bcr-Abl的表达对白血病细胞产生不同的影响，并选择性地增加bcr-abl表达的细胞的凋亡。
The Bcr-Abl fusion protein drives leukemogenesis and can render leukemia cells resistant to conventional chemotherapy. Geldanamycin (GA), a drug which destabilizes Hsp90-associated proteins, depletes cells of Bcr-Abl, an Hsp90 client, but not of Abl. Both HL60 cells transfected with Bcr-Abl and naturally Ph-positive K562 leukemia cells are resistant to most cytotoxic drugs, but were found to be sensitive to GA. Furthermore, GA sensitized Bcr-Abl-expressing cells to doxorubicin (DOX) and paclitaxel (PTX). In contrast, in parental HL60 cells, 90 nm GA inhibited PARP cleavage, nuclear fragmentation, and cell death caused by 500 ng/ml DOX. Like GA, STI 571 (an inhibitor of the Abl kinase) sensitized Bcr-Abl-expressing cells to DOX. Unlike GA, STI 571 did not antagonize the cytotoxic effects of DOX in parental HL60 cells. These results indicate that sensitization of Bcr-Abl-expressing cells, but not desensitization of HL60 cells, depends on inhibition of Bcr-Abl. Thus, GA differentially affects leukemia cells depending on their Bcr-Abl expression and selectively increases apoptosis in Bcr-Abl-expressing cells.