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新型组蛋白去乙酰化酶抑制剂与紫杉醇在体外和体内的协同抗肿瘤作用。

Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo.

机构信息

Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine, Fondazione Istituto Ricovero Cura Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy.

出版信息

PLoS One. 2011;6(12):e29085. doi: 10.1371/journal.pone.0029085. Epub 2011 Dec 14.

DOI:10.1371/journal.pone.0029085
PMID:22194993
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3241602/
Abstract

Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21(WAF1/Cip1) by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination.

摘要

临床前研究支持组蛋白去乙酰化酶抑制剂 (HDACi) 与紫杉烷类药物联合治疗的潜力。联合用药的疗效主要归因于微管蛋白乙酰化后微管的稳定作用。在本研究中，我们研究了紫杉醇与两种新型 HDACi（ST2782 或 ST3595）联合使用的效果，这两种新型 HDACi 能够诱导 p53 和微管蛋白过度乙酰化。在野生型 p53 卵巢癌细胞中，紫杉醇/ST2782（或 ST3595）联合具有协同作用，但在 p53 突变亚系中没有，尽管微管蛋白乙酰化明显。在其他含有野生型 p53 的人实体瘤细胞系中证实了这种协同相互作用，但在表达突变或缺失 p53 的细胞中没有。此外，当 ST2782 与去聚合剂长春瑞滨联合使用时，也发现了协同的细胞毒性作用。与 SAHA 相比，SAHA 对紫杉醇诱导的细胞凋亡的增敏作用要小得多，ST2782 可防止紫杉醇上调 p21(WAF1/Cip1)，p21(WAF1/Cip1)在紫杉烷类药物反应中具有保护作用，并导致 p53 下调、乙酰化和乙酰化 p53 的线粒体定位。在两种肿瘤异种移植模型中证实了紫杉醇/ST3595 联合的协同抗肿瘤作用。我们的研究结果支持 p53 调节作为观察到的紫杉醇与新型 HDACi 之间协同相互作用的主要决定因素的相关性，并强调了这种联合治疗的治疗意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/74fe5da7897f/pone.0029085.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/1911785398b2/pone.0029085.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/c7cdeae1c9b0/pone.0029085.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/74fe5da7897f/pone.0029085.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/7d9ed2cc725e/pone.0029085.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/ab100b73af87/pone.0029085.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/68a49cf4313d/pone.0029085.g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/c7cdeae1c9b0/pone.0029085.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/94f1/3241602/74fe5da7897f/pone.0029085.g007.jpg

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