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

doi:10.1038/s41401-021-00817-y

	FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11
	Yin, Yan-ping 1,2,3; Ma, Li-ying 1,2,3; Cao, Guo-zhen 1,2,3; Hua, Jing-han 1,2,3; Lv, Xiao-tong 1,2,3; Lin, Wen-chu 1,3
刊名	ACTA PHARMACOLOGICA SINICA
	2021-12-10
关键词	small cell lung cancer topotecan DNA damage response FK228 SLFN11 methylation epigenetic modulation
ISSN号	1671-4083
DOI	10.1038/s41401-021-00817-y
通讯作者	Lin, Wen-chu(wenchu@hmfl.ac.cn)
英文摘要	The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is similar to 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.
资助项目	National Natural Science Foundation of China[81972191] ; National Natural Science Foundation of China[81672647] ; Science and Technology Major Project of Anhui Province[18030801140] ; 100-Talent Program of Chinese Academy of Sciences ; High Magnetic Field Laboratory of Anhui Province
WOS关键词	RESISTANCE ; METHYLATION ; INHIBITION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000729050800002
资助机构	National Natural Science Foundation of China ; Science and Technology Major Project of Anhui Province ; 100-Talent Program of Chinese Academy of Sciences ; High Magnetic Field Laboratory of Anhui Province
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/126464]
专题	中国科学院合肥物质科学研究院
通讯作者	Lin, Wen-chu
作者单位	1.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China 2.Univ Sci & Technol China, Hefei 230026, Peoples R China 3.Chinese Acad Sci, Hefei Inst Phys Sci, High Field Magnet Lab, Hefei 230031, Peoples R China
推荐引用方式 GB/T 7714	Yin, Yan-ping,Ma, Li-ying,Cao, Guo-zhen,et al. FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11[J]. ACTA PHARMACOLOGICA SINICA,2021.
APA	Yin, Yan-ping,Ma, Li-ying,Cao, Guo-zhen,Hua, Jing-han,Lv, Xiao-tong,&Lin, Wen-chu.(2021).FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11.ACTA PHARMACOLOGICA SINICA.
MLA	Yin, Yan-ping,et al."FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11".ACTA PHARMACOLOGICA SINICA (2021).