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一种新型蛋白酶体抑制剂，作用于线粒体功能障碍、内质网应激和 ROS 产生。

A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production.

机构信息

Laboratório de Bioquímica e Biofísica- Instituto Butantan, Av. Vital Brazil, 1500-CEP, 05503-900, São Paulo, SP, Brazil.

出版信息

Invest New Drugs. 2013 Jun;31(3):493-505. doi: 10.1007/s10637-012-9871-1. Epub 2012 Sep 14.

DOI:10.1007/s10637-012-9871-1
PMID:22975862
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3644403/
Abstract

In cancer-treatment, potentially therapeutic drugs trigger their effects through apoptotic mechanisms. Generally, cell response is manifested by Bcl-2 family protein regulation, the impairment of mitochondrial functions, and ROS production. Notwithstanding, several drugs operate through proteasome inhibition, which, by inducing the accumulation and aggregation of misfolded or unfolded proteins, can lead to endoplasmic reticulum (ER) stress. Accordingly, it was shown that Amblyomin-X, a Kunitz-type inhibitor identified in the transcriptome of the Amblyomma cajennense tick by ESTs sequence analysis of a cDNA library, obtained in recombinant protein form, induces apoptosis in murine renal adenocarcinoma (RENCA) cells by: inducing imbalance between pro- and anti-apoptotic Bcl-2 family proteins, dysfunction/mitochondrial damage, production of reactive oxygen species (ROS), caspase cascade activation, and proteasome inhibition, all ER-stress inductive. Moreover, there was no manifest action on normal mouse-fibroblast cells (NHI3T3), suggesting an Amblyomin-X tumor-cell selectivity. Taken together, these evidences indicate that Amblyomin-X could be a promising candidate for cancer therapy.

摘要

在癌症治疗中，潜在的治疗药物通过细胞凋亡机制发挥作用。通常，细胞反应表现为 Bcl-2 家族蛋白调节、线粒体功能障碍和 ROS 产生。然而，一些药物通过蛋白酶体抑制起作用，这会导致错误折叠或未折叠蛋白质的积累和聚集，从而导致内质网（ER）应激。因此，研究表明，从 cDNA 文库的 ESTs 序列分析中鉴定出的 Amblyomma cajennense 蜱转录组中的 Kunitz 型抑制剂 Amblyomin-X，以重组蛋白形式获得，通过以下方式诱导鼠肾腺癌细胞（RENCA）凋亡：诱导促凋亡和抗凋亡 Bcl-2 家族蛋白之间的失衡、功能障碍/线粒体损伤、活性氧（ROS）的产生、半胱天冬酶级联激活和蛋白酶体抑制，所有这些都诱导内质网应激。此外，在正常的小鼠成纤维细胞（NHI3T3）中没有明显的作用，这表明 Amblyomin-X 对肿瘤细胞具有选择性。综上所述，这些证据表明 Amblyomin-X 可能是癌症治疗的有前途的候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/35f1232b4611/10637_2012_9871_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/5779acf51fc4/10637_2012_9871_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/eb216ad9b86a/10637_2012_9871_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/efbef0e579ff/10637_2012_9871_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/38a2b75b260a/10637_2012_9871_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/85355a046ae6/10637_2012_9871_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/bdfb2eaa2143/10637_2012_9871_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/059b327b5381/10637_2012_9871_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/35f1232b4611/10637_2012_9871_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/5779acf51fc4/10637_2012_9871_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/eb216ad9b86a/10637_2012_9871_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/efbef0e579ff/10637_2012_9871_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/38a2b75b260a/10637_2012_9871_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/85355a046ae6/10637_2012_9871_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/bdfb2eaa2143/10637_2012_9871_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/059b327b5381/10637_2012_9871_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/875f/3644403/35f1232b4611/10637_2012_9871_Fig8_HTML.jpg

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