A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-κB.
A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-κB.
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DOI：
10.1158/1078-0432.ccr-12-3510
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发表时间：
2013-09-15
期刊：
影响因子：
--
通讯作者：
Chaudhary PM
中科院分区：
文献类型：
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作者：
Gopalakrishnan R;Matta H;Chaudhary PM
卡波西肉瘤相关疱疹病毒（KSHV）相关原发性积液淋巴瘤（PEL）在常规化疗治疗时预后极差。kshv编码的病毒FLICE抑制蛋白（vFLIP） K13与IkappaB激酶（IKK）复合物结合，组成性地激活NF-κB通路，这对PEL细胞的存活和增殖至关重要。分子伴侣热休克蛋白90 （HSP90）是IKK复合体的一个组成部分，是其活性所必需的。我们分析了HSP90抑制剂对PEL细胞存活和增殖以及NF-κB通路活性的影响。我们证明了BIIB021，一种基于嘌呤支架的口服HSP90抑制剂，与非PEL细胞相比，对PEL细胞表现出优先的细胞毒性。BIIB021对PEL的细胞毒作用与诱导细胞周期阻滞和凋亡有关。BIIB021阻断了一些参与细胞周期和凋亡调控的细胞蛋白的表达。BIIB021还通过阻断vFLIP K13与IKK复合物亚基的相互作用，部分阻断了PEL细胞中存在的组成性NF-κB活性。在异种移植PEL模型中，BIIB021显著降低肿瘤生长。BIIB021阻断PEL中组成性NF-κB活性，并在体外和体内对PEL表现出优先的抗肿瘤活性。BIIB021可能是一种很有前景的治疗PEL的药物。
Kaposi's sarcoma associated herpesvirus (KSHV) associated primary effusion lymphomas (PEL) have extremely poor prognosis when treated with conventional chemotherapy. KSHV-encoded viral FLICE Inhibitory Protein (vFLIP) K13 binds to the IkappaB Kinase (IKK) complex to constitutively activate the NF-κB pathway, which has been shown to be essential for the survival and proliferation of PEL cells. The molecular chaperone Heat shock protein 90 (HSP90) is a component of the IKK complex and is required for its activity. We have analyzed the effect of HSP90 inhibitors on the survival and proliferation of PEL cells and on the activity of the NF-κB pathway. We demonstrate that BIIB021, a purine scaffold based orally administrable HSP90 inhibitor, shows preferential cytotoxicity towards PEL cells as compared to non-PEL cells. The cytotoxic effect of BIIB021 against PEL was associated with induction of cell-cycle arrest and apoptosis. BIIB021 blocked the expression of a number of cellular proteins involved in the regulation of cell-cycle and apoptosis. BIIB021 also blocked constitutive NF-κB activity present in PEL cells in part by blocking the interaction of vFLIP K13 with the IKK complex subunits. In a xenograft model of PEL, BIIB021 significantly reduced tumor growth. BIIB021 blocks constitutive NF-κB activity in PEL and demonstrate preferential anti-tumor activity against PEL in vitro and in vivo. BIIB021 may be a promising agent for treatment of PEL.