蛋白酶体抑制:跳出框框思考

M. B. Armstrong
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摘要

随着低毒性肿瘤特异性药物的开发,癌症治疗的新时代正在出现。自从伊马替尼问世以来,已经开发了几种针对肿瘤的治疗方案。然而,不专门针对肿瘤靶点的治疗也有潜在的益处。26S蛋白酶体通过降解包括p21、p27和p53在内的关键信号分子来调节细胞稳态。此外,蛋白酶体降解I-kB,从而抑制NF-kB的活性,NF-kB是细胞增殖的重要促进因子。蛋白酶体的阻断功能通过改变细胞从增殖到凋亡的平衡来破坏肿瘤的生长。在体外,蛋白酶体抑制剂硼替佐米(bortezomib)抑制NF-kB活性,并阻止包括多发性骨髓瘤在内的几种恶性细胞类型的生长。鉴于NF-kB在多发性骨髓瘤发病机制中的核心作用,硼替佐米是一个很好的治疗候选者。用硼替佐米治疗重度预处理患者的有效率为30%-40%。更重要的是,硼替佐米改善了骨代谢,这是多发性骨髓瘤发病的主要原因。这种效果与骨髓瘤的反应无关。这一发现与暴露于硼替佐米后BMP2表达和成骨细胞数量增加的体外研究相关。此外,硼替佐米阻断nf - kb介导的血管生成和肿瘤细胞转移。虽然肿瘤靶向治疗在未来的癌症治疗中具有重要作用,但这些例子表明,重要的是不要忽视非特异性药物在恶性肿瘤治疗中的益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Proteasome Inhibition: Thinking Outside the Box
A new era in cancer therapy is emerging with the development of tumor-specific agents exhibiting less toxicity. Since the advent of imatinib, several tumor-directed treatment options have been developed. However, therapies not directed specifically at a tumor target also have potential benefits. The 26S proteasome is a critical regulator of cell homeostasis through the degradation of key signaling molecules including p21, p27, and p53. Additionally, the proteasome degrades I-kB which inhibits the activity of NF-kB, an important promoter of cell proliferation. Blocking function of the proteasome disrupts tumor growth by shifting the balance of the cell from proliferation to apoptosis. In vitro, the proteasome inhibitor, bortezomib, inhibits NF-kB activity and prevents growth of several malignant cell types including multiple myeloma. Given the central role of NF-kB in the pathogenesis of multiple myeloma, bortezomib was a good candidate for use in therapy. Treatment of heavily pre-treated patients with bortezomib led to response rates of 30%–40%. More importantly, bortezomib led to improvements in bone metabolism, a major cause of morbidity in multiple myeloma. This effect was seen independent of the response of the myeloma. This finding correlates with in vitro studies which demonstrate increased BMP2 expression and osteoblast number after exposure to bortezomib. Moreover, bortezomib blocks NF-kB-mediated angiogenesis and tumor cell metastasis. While tumor-targeted treatments have an important role in the future of cancer therapy, these examples show that it is important not to lose sight of the benefits of less-specific agents in the treatment of malignant neoplasms.
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