摘要
肺癌是全球癌症相关死亡的主要原因。大多数肺癌患者诊断为晚期,可通过pembrolizumab (anti-PD-1 抗体)、细胞毒化疗及其他辅助治疗获益。尽管有各种各样的治疗方法,但反应率和存活率一直很低。因此,研究肺癌治疗的不同靶点一直是癌症研究的重点之一。泛素蛋白酶体系统(UPS)是细胞稳态的重要调节器,在所有细胞的生长发育中发挥着重要作用。UPS在包括肺癌细胞在内的人类癌细胞中是失调的。因此,锁定UPS可能是一种选择性的、有效的肺癌治疗方法。硼替佐米是一种20s蛋白酶体抑制剂,临床批准用于多发性骨髓瘤的治疗,已经在肺癌的各种临床前和临床模型中进行了研究。大多数临床前研究表明,单独使用20s蛋白酶体抑制剂及其与其他化疗药物联合使用可诱导非小细胞肺癌细胞系和动物模型的凋亡。由于较好的临床前结果,许多临床试验中开始使用20S蛋白酶体抑制剂作为单一治疗药物或与其他传统肺癌药物联合治疗。许多20s PIs与常规化疗的联合治疗在临床试验中显示出良好的耐受性。然而,没有任何数据显示以这些蛋白酶体抑制剂为基础的药物治疗效果。20s PIs在肺癌患者中的临床疗效低可能与低药物穿透、20s 蛋白酶体状态、癌基因表达和遗传或获得性耐药有关。肺癌细胞中PI耐药或低活性或无临床活性的潜在机制可能包括凋亡蛋白的改变、过表达或蛋白5亚基的改变,或热休克蛋白的上调。本文综述了对抗这种耐药或提高20s PIs在肺癌细胞中疗效的各种前沿策略,包括新颖的联合疗法、新的药物给药系统、开发更强的PIs,以及针对不同位点的UPS。更好地了解PI在肺癌细胞中的耐药机制,有助于改善目前的临床治疗策略和临床疗效。
关键词: 肺癌,非小细胞肺癌,小细胞肺癌,泛素蛋白酶体系统,蛋白酶体抑制剂,硼替佐米。
图形摘要
Current Cancer Drug Targets
Title:Updated Review and Perspective on 20S Proteasome Inhibitors in the Treatment of Lung Cancer
Volume: 20 Issue: 6
关键词: 肺癌,非小细胞肺癌,小细胞肺癌,泛素蛋白酶体系统,蛋白酶体抑制剂,硼替佐米。
摘要:
Lung cancer is the leading cause of cancer-related deaths worldwide. Most lung cancer patients are diagnosed at advanced stages and may benefit from pembrolizumab (anti-PD-1 antibody), cytotoxic chemotherapy and other adjuvant therapies. Despite the availability of various therapies, the response and survival rates have been low. Therefore, the study of different targets for the treatment of lung cancer has been one of the major focuses of cancer research.
The ubiquitin proteasome system (UPS) is a crucial regulator of cell homeostasis and plays an essential role in the growth and development of all cells. The UPS is dysregulated in human cancer cells including lung cancer cells. Therefore, targeting UPS is potentially a selective, effective treatment for lung cancer. Bortezomib, a 20S proteasome inhibitor that is clinically approved for the management of multiple myeloma, has been studied in various preclinical and clinical models of lung cancer.
Most preclinical studies have shown that a 20S proteasome inhibitor alone and its combination with other chemotherapeutic agents induce apoptosis in non-small cell lung cancer cell lines and animal models. Owing to the impressive preclinical results, many clinical trials were initiated using 20S proteasome inhibitors either as monotherapy or in combination with other conventional lung cancer therapies. Many combinational therapies of 20S PIs with conventional chemotherapy were shown to be well tolerated in clinical trials. However, there have not been any consistent data showing the beneficial effects of such proteasome inhibitor-based therapies. Low clinical efficacy of 20S PIs in lung cancer patients may be due to low drug penetration, the status of 20S proteasomes, oncogene expressions and the inherited or acquired resistance. Potential mechanisms of PI resistance or low or no clinical activity in lung cancer cells might include alteration of apoptotic proteins, overexpression or alteration of β5 subunit, or upregulation of heat shock proteins. Various cutting-edge strategies to counter this resistance or improve 20S PIs’ efficacy in lung cancer cells have been reviewed which include novel combination therapies, new drug delivery systems, development of more potent PIs, and targeting different sites of the UPS. A better understanding of PI resistance mechanisms in lung cancer cells can help improve current clinical treatment strategies and clinical outcomes.
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Cite this article as:
Updated Review and Perspective on 20S Proteasome Inhibitors in the Treatment of Lung Cancer, Current Cancer Drug Targets 2020; 20 (6) . https://dx.doi.org/10.2174/1568009620666200226094000
DOI https://dx.doi.org/10.2174/1568009620666200226094000 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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