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比较用于卵巢癌治疗的PI3K/Akt抑制剂

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment.

作者信息

Wu Yi-Hui, Huang Yu-Fang, Chen Chien-Chin, Huang Chia-Yen, Chou Cheng-Yang

机构信息

Department of Medical Research, Chi Mei Medical Center, Liouying, Taiwan.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

出版信息

Front Pharmacol. 2020 Mar 3;11:206. doi: 10.3389/fphar.2020.00206. eCollection 2020.

DOI:10.3389/fphar.2020.00206
PMID:32194423
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7063971/
Abstract

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.

摘要

上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤。在此，我们试图在NOD-SCID异种移植小鼠模型中确定使用三种AZD化合物抑制磷酸肌醇3激酶（PI3K）/Akt的效果，并在一组八种卵巢癌细胞系中研究Akt的调控情况。癌组织中Ser473位点而非Thr308位点的Akt磷酸化水平升高与无进展生存期（PFS）缩短、总生存期（OS）缩短及死亡相关。AZD8835和AZD8186抑制Akt磷酸化，而AZD5363增强其在Ser473位点的磷酸化。此外，所有化合物均抑制Akt下游效应分子4E-BP1和p70S6激酶。AZD8835和AZD5363使化疗耐药的卵巢癌细胞对顺铂和紫杉醇治疗敏感。只有AZD5363能够抑制COL11A1 mRNA及启动子活性，而COL11A1是卵巢癌中Akt调控及化疗耐药的重要因素。通过使用小鼠异种移植模型，AZD8835和AZD5363（而非AZD8186）可显著减少肿瘤形成。AZD化合物未改变卵巢癌细胞中BRCA1/BRCA的mRNA表达，但AZD8835可抑制携带 突变的OVCAR-8细胞中BRCA1/BRCA2 mRNA表达及p-ERK蛋白表达。本研究强调了PI3K/Akt在卵巢肿瘤进展和化疗耐药中的重要性，以及AZD化合物，尤其是AZD8835和AZD5363作为卵巢癌治疗药物的潜在应用价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6cf1/7063971/09451ecb5644/fphar-11-00206-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6cf1/7063971/0331341c1f4b/fphar-11-00206-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6cf1/7063971/09451ecb5644/fphar-11-00206-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6cf1/7063971/0331341c1f4b/fphar-11-00206-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6cf1/7063971/987828f29d70/fphar-11-00206-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6cf1/7063971/45400d224db8/fphar-11-00206-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6cf1/7063971/09451ecb5644/fphar-11-00206-g005.jpg

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