Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-κB with antimyeloma activity in vitro and in vivo
Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-κB with antimyeloma activity in vitro and in vivo
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DOI：
10.1182/blood-2008-09-179796
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发表时间：
2009-04-23
期刊：
影响因子：
20.3
通讯作者：
Stewart, A. Keith
中科院分区：
文献类型：
--
作者：
Tiedemann, Rodger E.;Schmidt, Jessica;Stewart, A. Keith
由于多发性骨髓瘤肿瘤普遍失调细胞周期蛋白 D 基因，我们对诱导细胞周期蛋白 D2 启动子转录抑制的化合物进行了高通量化学库筛选。排名第一的化合物是一种天然三萜类化合物普里斯蒂莫林。引人注目的是，用 pritimerin 处理的细胞的早期转录反应与蛋白酶体抑制剂引起的细胞反应非常相似，快速诱导热休克蛋白，激活转录因子 3 (ATF3) 和 CHOP。酶测定和免疫印迹证实，pritimerin 在低浓度 (< 100 nM) 下可快速（< 90 分钟）且特异性地抑制胰凝乳蛋白酶样蛋白体活性，并导致细胞泛素化蛋白的积累。值得注意的是，包括 pritimerin 在内的细胞毒性三萜类化合物通过抑制 IKK α 或 IKK β 来抑制 NF-κ B 激活，而蛋白体抑制剂则通过损害泛素化 I kappa B 的降解来抑制 NF-κ B 功能。通过抑制 IKK 和蛋白酶体，pritimerin 会明显抑制骨髓瘤细胞中的组成型 NF-κ B 活性，从而可能介导其细胞周期蛋白 D 的抑制。多发性骨髓瘤对蛋白酶体或 NF-kappa B 通路抑制极其敏感。与此一致的是，pritimerin 对原发性骨髓瘤细胞具有有效和选择性的致死作用 (IC(50) < 100 nM)，抑制小鼠异种移植的浆细胞瘤，并与硼替佐米具有协同细胞毒性，这为三萜类双功能蛋白酶体/NF-κ B 抑制剂作为人类多发性骨髓瘤和相关恶性肿瘤的治疗药物的药物开发提供了理论基础。 （血。2009；113：4027-4037）
As multiple myeloma tumors universally dysregulate cyclin D genes we conducted high-throughput chemical library screens for compounds that induce suppression of cyclin D2 promoter transcription. The top-ranked compound was a natural triterpenoid, pristimerin. Strikingly, the early transcriptional response of cells treated with pristimerin closely resembles cellular responses elicited by proteosome inhibitors, with rapid induction of heat shock proteins, activating transcription factor 3 (ATF3), and CHOP. Enzymatic assays and immunoblotting confirm that pristimerin rapidly (< 90 minutes) and specifically inhibits chymotrypsin-like proteosome activity at low concentrations (< 100 nM) and causes accumulation of cellular ubiquitinated proteins. Notably, cytotoxic triterpenoids including pristimerin inhibit NF-kappa B activation via inhibition of IKK alpha or IKK beta, whereas proteosome inhibitors instead suppress NF-kappa B function by impairing degradation of ubiquitinated I kappa B. By inhibiting both IKK and the proteosome, pristimerin causes overt suppression of constitutive NF-kappa B activity in myeloma cells that may mediate its suppression of cyclin D. Multiple myeloma is exquisitely sensitive to proteosome or NF-kappa B pathway inhibition. Consistent with this, pristimerin is potently and selectively lethal to primary myeloma cells (IC(50) < 100 nM), inhibits xenografted plasmacytoma tumors in mice, and is synergistically cytotoxic with bortezomib-providing the rationale for pharmaceutical development of triterpenoid dual-function proteosome/NF-kappa B inhibitors as therapeutics for human multiple myeloma and related malignancies. (Blood. 2009;113:4027-4037)