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探索线粒体凋亡性细胞死亡格局及作为分子靶点的相关成分,主要针对用于肿瘤治疗的合成药物和天然药物。

Exploring the Mitochondrial Apoptotic Cell Death Landscape and Associated Components Serving as Molecular Targets, Primarily for Synthetic and Natural Drugs Targeting Oncology Therapeutics.

作者信息

Kaur Ishnoor, Behl Tapan, Sachdeva Monika, Bungau Simona, Venkatachalam Thangavel

机构信息

Chitkara College of Pharmacy, Chitkara University, Punjab,India.

Fatima College of Health Sciences, Al Ain,United Arab Emirates.

出版信息

Curr Mol Pharmacol. 2021;14(6):1066-1082. doi: 10.2174/1874467214666210120145537.

DOI:10.2174/1874467214666210120145537
PMID:33494688
Abstract

The role of mitochondria in the apoptosis signaling cell death pathway is regulated by extrinsic and intrinsic pathway, encompassing multiple components like the Bcl-2 family of proteins, death receptors, caspases, Smac/DIABLO, IAPs, Omi/HtrA2 and cytochrome c. These entities serve as effective molecular targets for numerous drugs targeting mitochondrial apoptotic pathways, mainly emphasizing oncology therapeutics. Defective apoptosis is an acquired hallmark of cancer cells, which promotes the establishment of apoptosis-targeting anti-cancer drugs in cancer treatment. The review provides an overview of the Bcl-2 inhibiting, IAPs antagonizing, caspase inhibiting and BH3 mimicking actions, mediated by anti-cancer drugs, rendering beneficial outcomes in different forms of cancer. The authors elaborate on the significance of synthetic and natural agents, targeting the mitochondrial apoptotic pathway, in ameliorating tumor cell growth in the body, and the specificity and effectiveness of these agents, motivating the researchers to explore mitochondrial apoptosis targeting of anti-tumor drugs of both herbal and synthetic origin. Thus, the review aims to predict this dynamic approach in oncology, simultaneously highlighting the challenges and future prospects, providing an opportunity to the experts to "go over with a fine tooth comb" in understanding this "programmed cell death pathway", and establishing reliability and accuracy of this therapeutic paradigm in the upcoming future.

摘要

线粒体在凋亡信号传导细胞死亡途径中的作用受外在和内在途径调控,涉及多种成分,如Bcl-2蛋白家族、死亡受体、半胱天冬酶、Smac/DIABLO、IAPs、Omi/HtrA2和细胞色素c。这些实体是众多靶向线粒体凋亡途径药物的有效分子靶点,主要侧重于肿瘤治疗。凋亡缺陷是癌细胞的一个后天特征,这促进了在癌症治疗中建立靶向凋亡的抗癌药物。本综述概述了抗癌药物介导的Bcl-2抑制、IAPs拮抗、半胱天冬酶抑制和BH3模拟作用,在不同形式的癌症中产生了有益的结果。作者阐述了靶向线粒体凋亡途径的合成和天然药物在改善体内肿瘤细胞生长方面的意义,以及这些药物的特异性和有效性,激励研究人员探索源自草药和合成药物的抗肿瘤药物对线粒体凋亡的靶向作用。因此,本综述旨在预测肿瘤学中的这种动态方法,同时突出挑战和未来前景,为专家提供一个“仔细梳理”的机会,以理解这种“程序性细胞死亡途径”,并在未来确立这种治疗模式的可靠性和准确性。

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Exploring the Mitochondrial Apoptotic Cell Death Landscape and Associated Components Serving as Molecular Targets, Primarily for Synthetic and Natural Drugs Targeting Oncology Therapeutics.探索线粒体凋亡性细胞死亡格局及作为分子靶点的相关成分,主要针对用于肿瘤治疗的合成药物和天然药物。
Curr Mol Pharmacol. 2021;14(6):1066-1082. doi: 10.2174/1874467214666210120145537.
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Bax/Bak-dependent, Drp1-independent Targeting of X-linked Inhibitor of Apoptosis Protein (XIAP) into Inner Mitochondrial Compartments Counteracts Smac/DIABLO-dependent Effector Caspase Activation.依赖Bax/Bak、不依赖Drp1将X连锁凋亡抑制蛋白(XIAP)靶向输送至线粒体内腔室可抵消Smac/DIABLO依赖性效应半胱天冬酶的激活。
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Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2.Smac/DIABLO从线粒体的凋亡相关释放需要活性半胱天冬酶,并且被Bcl-2阻断。
EMBO J. 2001 Dec 3;20(23):6627-36. doi: 10.1093/emboj/20.23.6627.
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Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis.半胱天冬酶-3的第二个线粒体衍生激活剂(Smac/DIABLO)的异位过表达或与Smac/DIABLO肽的N端共同处理可增强埃坡霉素B衍生物(BMS 247550)和Apo-2L/TRAIL诱导的细胞凋亡。
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Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway.Smac/DIABLO促进半胱天冬酶活性的分子决定因素及其在死亡受体途径中的作用。
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Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria.Bax通过控制Smac/Diablo和Omi/HtrA2从线粒体的释放,在毒胡萝卜素诱导的人结肠癌HCT116细胞凋亡中起关键作用。
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Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway.Akt介导的卵巢癌顺铂耐药:p53对依赖半胱天冬酶的线粒体死亡途径作用的调节
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Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways.线粒体蛋白酶Omi/HtrA2通过多种途径增强半胱天冬酶的激活。
Cell Death Differ. 2004 Feb;11(2):208-16. doi: 10.1038/sj.cdd.4401343.

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