CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance
Publication in refereed journal

香港中文大學研究人員
替代計量分析
.

其它資訊
摘要Platinum (Pt)-based anticancer drugs are the mainstay of treatment for solid cancers. However, resistance to Pt drugs develops rapidly, which can be caused by overexpression of multidrug resistance transporters and activation of DNA repair. CUDC-907 is a potent molecular targeted anticancer agent, rationally designed to simultaneously inhibit histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K). We investigated the potentiation effect of CUDC-907 on Pt drugs in resistant cancer cells. ABCC2 stably-transfected HEK293 cells and two pairs of parental and Pt-resistant cancer cell lines were used to test for the circumvention of resistance by CUDC-907. Chemosensitivity was assessed by the sulphorhodamine B assay. Drug combinations were evaluated by the median effect analysis. ABCC2 transport activity was examined by flow cytometric assay. Cellular Pt drug accumulation and DNA platination were detected by inductively coupled plasma optical emission spectroscopy. ABCC2, ERCC1 and p21 expression were evaluated by quantitative real-time PCR. Cell cycle analysis and apoptosis assay were performed by standard flow cytometric method. The combination of CUDC-907 with cisplatin were found to exhibit synergistic cytotoxic effect in cisplatin-resistant cancer cells. In Pt-resistant cancer cells, CUDC-907 apparently circumvented the resistance through inhibition of ABCC2 and DNA repair but induction of cell cycle arrest. In the presence of CUDC-907, cellular accumulation of Pt drugs and formation of DNA-Pt adducts were found to be increased whereas expression levels of ABCC2 and ERCC1 was inhibited in Pt-resistant cells. The data advocates further development of CUDC-907 as a resistance reversal agent for use in combination cancer chemotherapy.
著者Kenneth K. W. To, Li-wu Fu
期刊名稱Investigational New Drugs
出版年份2018
月份2
卷號36
期次1
頁次10 - 19
國際標準期刊號0167-6997
電子國際標準期刊號1573-0646
語言美式英語
關鍵詞CUDC-9017, Platinum anticancer drug, Drug resistance, Efflux transporters, DNA repair

上次更新時間 2020-23-11 於 01:43