PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells.
PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells.
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DOI：
10.1158/1535-7163.mct-10-0141
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发表时间：
2010-07
影响因子：
5.7
通讯作者：
Wang CY
中科院分区：
文献类型：
--
作者：
Kim J;Guan J;Chang I;Chen X;Han D;Wang CY
蛋白酶体抑制剂PS-341（也称为Bortezaldehyde）和组蛋白脱乙酰酶（HDAC）抑制剂已成为各种恶性肿瘤的新型治疗药物。在这项研究中，我们研究了PS-341和HDAC抑制剂阿司他丁A（TSA）是否诱导头颈部鳞状细胞癌（HNSCC）细胞凋亡，HNSCC是一种常见的致命恶性肿瘤。我们发现，虽然TSA单独处理不诱导HNSCC细胞凋亡，但它在体外显著增强PS-341诱导的HNSCC细胞凋亡。因此，TSA显著改善了PS-341介导的对裸鼠中HNSCC肿瘤生长的抑制。从机制上讲，我们发现TSA增加了PS-341诱导的HNSCC细胞中Noxa表达和半胱天冬酶活化。敲低Noxa显著降低了PS-341和TSA共处理诱导的细胞凋亡。综上所述，我们的研究结果为PS-341和HDAC抑制剂方案的协同抗肿瘤活性机制提供了新的见解，为HNSCC患者提供了新的治疗策略。
Proteasome inhibitor PS-341 (also known as Bortezomib) and histone deacetylase (HDAC) inhibitors have emerged as novel therapeutic agents for a variety of malignancies. In this study, we examined whether PS-341 and the HDAC inhibitor trichostatin A (TSA) induced apoptosis in head and neck squamous cell carcinoma (HNSCC), a common and lethal malignancy. We found that, while TSA treatment alone did not induce apoptosis in HNSCC cells, it significantly enhanced PS-341-induced apoptosis in HNSCC cells in vitro. Consistently, TSA significantly improved PS-341-mediated inhibition of HNSCC tumor growth in nude mice. Mechanistically, we found that TSA increased PS-341-induced Noxa expression and caspase activation in HNSCC cells. The knock-down of Noxa significantly reduced apoptosis induced by co-treatment of PS-341 and TSA. Taken together, our results provide new insight into the mechanisms of synergistic antitumor activity of PS-341 and HDAC inhibitor regimen, offering a new therapeutic strategy for HNSCC patients.