Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Curr Drug Targets. 2009 Oct;10(10):968-81. doi: 10.2174/138945009789577909.
The ubiquitin-proteasome pathway is involved in intracellular protein turnover and plays an essential function in many cellular processes, thus contributing to cellular homeostasis. The observation that proteasome inhibitors are able to induce apoptosis preferentially in tumor cells opened the way to their use as potential drugs. One of these drugs, bortezomib, was introduced in cancer therapy and its use was approved for the treatment of multiple myeloma and mantle cell lymphoma. The investigation of the mechanisms through which bortezomib causes cell death of cancer cells showed that this drug affects many cellular pathways and many of its effects cannot be related to proteasome inhibition. These observations, as well as the occurrence of bortezomib resistance observed in some myeloma patients treated with this drug, prompted the study of new proteasome inhibitors. These studies have lead to a new generation of proteasome inhibitors, some of them exhibiting the property of selective proteasome inhibition and efficacy in cancer therapy without inducing the side effects elicited by bortezomib. The ensemble of these drugs offers the scenario of the possible development of a family of proteasome inhibitors, contributing a drug arsenal for the therapy of cancer and other diseases.
泛素-蛋白酶体途径参与细胞内蛋白质周转，在许多细胞过程中发挥着重要作用，从而有助于细胞内的稳态。蛋白酶体抑制剂能够优先诱导肿瘤细胞凋亡这一观察结果为将其用作潜在药物开辟了道路。其中一种药物硼替佐米已被引入癌症治疗中，并被批准用于治疗多发性骨髓瘤和套细胞淋巴瘤。研究硼替佐米导致癌细胞死亡的机制表明，该药物影响许多细胞途径，其许多作用不能与蛋白酶体抑制相关。这些观察结果，以及在一些接受该药物治疗的骨髓瘤患者中观察到的硼替佐米耐药性的发生，促使人们研究新的蛋白酶体抑制剂。这些研究导致了新一代蛋白酶体抑制剂的出现，其中一些抑制剂具有选择性蛋白酶体抑制作用和在癌症治疗中的功效，而不会引起硼替佐米引起的副作用。这些药物的组合为开发蛋白酶体抑制剂家族提供了可能，为癌症和其他疾病的治疗提供了药物武器库。
