针对癌症治疗的生存素:开发中的策略、小分子抑制剂和疫苗治疗。

Targeting survivin for cancer therapy: Strategies, small molecule inhibitors and vaccine based therapeutics in development.

机构信息

Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.

Institute for Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany.

出版信息

Life Sci. 2023 Dec 15;335:122260. doi: 10.1016/j.lfs.2023.122260. Epub 2023 Nov 12.

Abstract

Survivin is a member of the family of inhibitors of apoptosis proteins (IAPs). It is involved in the normal mitotic process and acts as an anti-apoptotic molecule. While terminally differentiated normal tissues lack survivin, several human malignancies have significant protein levels. Resistance to chemotherapy and radiation in tumor cells is associated with survivin expression. Decreased tumor development, apoptosis, and increased sensitivity to chemotherapy and radiation are all effects of downregulating survivin expression or activity. As a prospective cancer treatment, small molecules targeting the transcription and translation of survivin and molecules that can directly bind with the survivin are being explored both in pre-clinical and clinics. Pre-clinical investigations have found and demonstrated the effectiveness of several small-molecule survivin inhibitors. Unfortunately, these inhibitors have also been shown to have off-target effects, which could limit their clinical utility. In addition to small molecules, several survivin peptide vaccines are currently under development. These vaccines are designed to elicit a cytotoxic T-cell response against survivin, which could lead to the destruction of tumor cells expressing survivin. Some survivin-based vaccines are advancing through Phase II clinical studies. Overall, survivin is a promising cancer drug target. However, challenges still need to be addressed before the survivin targeted therapies can be widely used in the clinics.

摘要

Survivin 是凋亡抑制蛋白(IAPs)家族的成员。它参与正常的有丝分裂过程,并作为一种抗凋亡分子起作用。虽然终末分化的正常组织缺乏 survivin,但几种人类恶性肿瘤具有显著的蛋白水平。肿瘤细胞对化疗和放疗的耐药性与 survivin 的表达有关。下调 survivin 的表达或活性可导致肿瘤发展减少、细胞凋亡增加以及对化疗和放疗的敏感性增加。作为一种有前途的癌症治疗方法,目前正在临床前和临床中探索针对 survivin 的转录和翻译的小分子以及可以直接与 survivin 结合的分子。临床前研究已经发现并证明了几种小分子 survivin 抑制剂的有效性。不幸的是,这些抑制剂也显示出脱靶效应,这可能限制它们的临床应用。除了小分子外,目前还在开发几种 survivin 肽疫苗。这些疫苗旨在针对 survivin 引发细胞毒性 T 细胞反应,从而导致表达 survivin 的肿瘤细胞被破坏。一些基于 survivin 的疫苗正在进行 II 期临床试验。总的来说,survivin 是一种很有前途的癌症药物靶点。然而,在 survivin 靶向治疗能够广泛应用于临床之前,仍需要解决一些挑战。

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