Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts
Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts
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DOI：
10.1038/sj.cdd.4400436
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发表时间：
1998-12-01
影响因子：
12.4
通讯作者：
Dou, QP
中科院分区：
文献类型：
--
作者：
An, B;Goldfarb, RH;Dou, QP
有人提出，在人类癌细胞中Bcl - 2癌蛋白的过度表达导致其对化疗诱导的细胞凋亡产生抗性。我们在此报道，一种新型的二肽基蛋白酶体抑制剂CEP1612，在低浓度时能迅速诱导过度表达Bcl - 2的人类Jurkat T细胞凋亡，并且在我们迄今为止所测试的所有人类前列腺、乳腺、舌部和脑部肿瘤细胞系中无一例外地诱导凋亡。相比之下，依托泊苷这种标准的抗癌药物在相同条件下无法杀死这些细胞。CEP1612及其类似化合物诱导细胞凋亡的能力与其对蛋白酶体糜蛋白酶样活性的抑制顺序完全一致。CEP1612诱导的细胞凋亡不依赖p53，可被一种四肽半胱天冬酶抑制剂抑制，并且与细胞周期蛋白依赖性激酶抑制剂p21和p27的积累有关。此外，CEP1612选择性地使p27积累，并在猿猴病毒40转化的人类成纤维细胞中诱导细胞凋亡，但在其亲本正常的人类成纤维细胞中则不会。因此，像本文所研究的这类蛋白酶体抑制剂可能有作为新型抗癌药物的潜在用途。
It has been suggested that overexpression of the Bcl-2 oncoprotein in human cancer cells contributes to their resistance to apoptosis induced by chemotherapy, We report here that a novel dipeptidyl proteasome inhibitor, CEP1612, at low concentrations rapidly induces apoptosis in human Jurkat T cells overexpressing Bcl-2 and also in ail human prostate, breast, tongue and brain tumor cell lines we have tested to date, without exception. In contrast, etoposide, a standard anticancer drug, fails to kill these cells when employed under the same conditions. The apoptosis-inducing abilities of CEP1612 and its analogous compounds match precisely their order for inhibition of the proteasome chymotrypsin-like activity. CEP1612-induced apoptosis is p53-independent, inhibitable by a tetrapeptide caspase inhibitor, and associated with accumulation of the cyclin-dependent kinase inhibitors p21 and p27. Furthermore, CEP1612 selectively accumulates p27 and induces apoptosis in simian virus 40-transformed, but not the parental normal, human fibroblasts. Proteasome inhibitors such as those investigated herein might therefore have potential use as novel anticancer drugs.