D'Alessandro Annamaria, Pieroni Luisa, Ronci Maurizio, D'Aguanno Simona, Federici Giorgio, Urbani Andrea
IRCCS-Fondazione Santa Lucia Centro di Ricerca sul Cervello, Rome, Italy.
Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):73-82. doi: 10.2174/157489209787002452.
Aberrations in the Ubiquitin-Proteasome System (UPS) have been recently connected to the pathogenesis of several human protein degradation disorders (e.g., cancer and neurodegenerative diseases), so that proteasome is now considered an important target for drug discovery. Small molecules able to inhibit and modulate UPS have been, in fact, described as novel tools for a new approach in anti-cancer therapy. In particular Proteasome Inhibitors (PIs), blocking activation of nuclear factor-kappa B (NF-kB), trigger a decreased cellular proliferation and angiogenic cytokine production, induce cell death and inhibit tumor cell adhesion to stroma. Furthermore, several studies have demonstrated that PIs potentiate the activity of other anti-cancer treatment, in part by down-regulating chemoresistance pathways. Therefore pharmacologic, preclinical, and clinical data suggested the use of PIs in anticancer strategies, for their potential therapeutic relevance in the treatment of cancer and inflammatory-related diseases. This review focuses on recent advances in the development of PIs anticancer agents highlighting both novel patented compounds and novel therapeutic protocol of intervention.
泛素-蛋白酶体系统（UPS）的异常最近已与几种人类蛋白质降解紊乱（如癌症和神经退行性疾病）的发病机制相关联，因此蛋白酶体现在被认为是药物研发的重要靶点。事实上，能够抑制和调节UPS的小分子已被描述为抗癌治疗新方法的新型工具。特别是蛋白酶体抑制剂（PIs），通过阻断核因子-κB（NF-κB）的激活，触发细胞增殖减少和血管生成细胞因子产生，诱导细胞死亡并抑制肿瘤细胞与基质的粘附。此外，多项研究表明，PIs可增强其他抗癌治疗的活性，部分原因是下调化疗耐药途径。因此，药理学、临床前和临床数据表明，PIs因其在癌症和炎症相关疾病治疗中的潜在治疗相关性，可用于抗癌策略。本综述重点关注PIs抗癌药物开发的最新进展，突出新型专利化合物和新型治疗干预方案。
