HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance
HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance
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DOI：
10.1182/blood.v95.7.2378.007k10_2378_2385
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发表时间：
2000-04-01
期刊：
影响因子：
20.3
通讯作者：
Johnstone, RW
中科院分区：
文献类型：
--
作者：
Ruefli, AA;Smyth, MJ;Johnstone, RW
多药耐药（MDR）通常以p -糖蛋白（P-gp）的表达为特征，p -糖蛋白是一种170 kd的atp依赖性药物外排蛋白。除了外排的异种毒素外，功能性P-gp还可以抵抗一系列不同刺激诱导的caspase依赖性凋亡，包括Fas配体、肿瘤坏死因子、紫外线照射和血清饥饿。然而，p- gp阳性细胞对细胞毒性t细胞颗粒蛋白、perforin和颗粒酶b诱导的caspase非依赖性死亡仍然敏感。因此，以caspase非依赖性方式诱导细胞死亡的药物可能会绕过p- gp介导的MDR。我们在这里证明，在浓度为10 mmol/L及以上的p- gp阳性和阴性细胞系中，六亚甲基双乙酰胺（HMBA）诱导了同等的caspase非依赖性细胞死亡。hmba诱导的死亡途径以线粒体细胞色素c的释放和Bcl-2蛋白水平的降低为标志。此外，我们发现功能性P-gp特异性抑制特定半胱天冬酶的激活，如caspase- 8和-3，而其他半胱天冬酶，如caspase-9，则不受影响。这些研究极大地增强了我们对功能性P-gp可调控的分子细胞死亡事件的理解，并强调了通过caspase非依赖性途径治疗Mon肿瘤的药物的潜在临床应用。（Blood, 2000;95:2378-2385） (C) 2000由美国血液学会出版。
Multidrug resistance (MDR) is often characterized by the expression of P-glycoprotein (P-gp), a 170-kd ATP-dependent drug efflux protein. As well as effluxing xenotoxins, functional P-gp can confer resistance to caspase-dependent apoptosis induced by a range of different stimuli, including Fas ligand, tumor necrosis factor, UV irradiation, and serum starvation. However, P-gp-positive cells remain sensitive to caspase-independent death induced by cytotoxic T-cell granule proteins, perforin, and granzyme B. It is, therefore, possible that agents that induce cell death in a caspase-independent manner might circumvent P-gp-mediated MDR, We demonstrated here that hexamethylene bisacetamide (HMBA) induced equivalent caspase-independent cell death in both P-gp-positive and -negative cell lines at concentrations of 10 mmol/L and above. The HMBA-induced death pathway was marked by release of cytochrome c from the mitochondria and reduction of Bcl-2 protein levels. In addition, we show that functional P-gp specifically inhibits the activation of particular caspases, such as caspases-8 and -3, whereas others, such as caspase-9, remain unaffected. These studies greatly enhance our understanding of the molecular cell death events that can be regulated by functional P-gp and highlight the potential clinical use of drugs that function via a caspase-independent pathway for the treatment of Mon tumors, (Blood, 2000;95:2378-2385) (C) 2000 by The American Society of Hematology.