Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment

doi:10.3389/fphar.2020.00206

Chia Nan University of Pharmacy & Science Institutional Repository > 藥理學院 > 化妝品應用與管理系(所) > 期刊論文 > Item 310902800/34114

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標題:	Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment
作者:	Wu, Yi-Hui Huang, Yu-Fang Chen, Chien-Chin Huang, Chia-Yen Chou, Cheng-Yang
貢獻者:	Chi Mei Med Ctr, Dept Med Res Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Coll Med, Dept Obstet & Gynecol Chia Yi Christian Hosp, Dept Pathol, Ditmanson Med Fdn Chia Nan Univ Pharm & Sci, Dept Cosmet Sci Natl Chiao Tung Univ, Coll Biol Sci & Technol, Dept Biol Sci & Technol Cathay Gen Hosp, Gynecol Canc Ctr, Dept Obstet & Gynecol Fu Jen Catholic Univ, Sch Med
關鍵字:	epithelial ovarian carcinoma chemoresistance PI3K inhibitor Akt inhibitor cisplatin paclitaxel
日期:	2020
上傳時間:	2022-11-18 11:24:28 (UTC+8)
出版者:	Frontiers Media Sa
摘要:	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 KRAS 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.
關聯:	Frontiers In Pharmacology, v.11, pp.16
显示于类别:	[化妝品應用與管理系(所)] 期刊論文

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