FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11  

作　　者：Yan-ping Yin Li-ying Ma Guo-zhen Cao Jing-han Hua Xiao-tong Lv Wen-chu Lin 

机构地区：[1]High Magnetic Field Laboratory,Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei,230031,China [2]University of Science and Technology of China,Hefei,230026,China [3]Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei,230031,China

出　　处：《Acta Pharmacologica Sinica》2022年第8期2119-2127,共9页中国药理学报（英文版）

基　　金：supported by National Natural Science Foundation of China(81972191 and 81672647);Science and Technology Major Project of Anhui Province(18030801140);the 100-Talent Program of Chinese Academy of Sciences.

摘　　要：The response rate of topotecan,as a second-line chemotherapeutic drug for small cell lung cancer,is~20%.DNA/RNA helicase SLFN11(schlafen family member 11),a member of the Schlafen(SLFN)family,is a crucial determinant of response to many DNA damaging agents,expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents.In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan.We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines.Topotecan treatment induced different patterns of the DNA response network in SCLC cells:DNA damage response(DDR)was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273,whereas topotecan induced significant accumulation of p-Chk1,p-RPA2 and Rad51 in H82 cells,but not in DMS273 cells.We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter.HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter,thereby sensitizing SCLC cells to topotecan.Finally,we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens,and found that most of the clinical samples(24/27)showed DNA methylation at the SLFN11 promoter.In conclusion,it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.

关 键 词：small cell lung cancer TOPOTECAN DNA damage response FK228 SLFN11 METHYLATION epigenetic modulation 

分 类 号：R734.2[医药卫生—肿瘤]