Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer

doi:10.1038/s41401-020-00544-w

	Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer
	Yin, Yan-ping 1,2,8; Shi, Wen-hao 3; Deng, Ke 1,2,8; Liu, Xiao-li 1,2,8; Li, Hong 2,8; Lv, Xiao-tong 1,2,8; Lui, Vivian Wai Yan 4; Ding, Chen 5,6,7; Hong, Bo 2,8; Lin, Wen-chu 2,8
刊名	ACTA PHARMACOLOGICA SINICA
	2020-11-02
关键词	small cell lung cancer obatoclax bortezomib carfilzomib MCL-1 apoptosis FOXM1 proteomics analysis
ISSN号	1671-4083
DOI	10.1038/s41401-020-00544-w
通讯作者	Ding, Chen(chend@fudan.edu.cn) ; Hong, Bo(bhong@hmfl.ac.cn) ; Lin, Wen-chu(wenchu@hmfl.ac.cn)
英文摘要	Proteasome inhibitors, bortezomib (BTZ), and carfilzomib (CFZ) are approved drugs for hematological malignancies, but lack anticancer activities against most solid tumors. Small cell lung cancer (SCLC) is a very aggressive neuroendocrine carcinoma of the lungs demanding effective therapy. In this study we investigated whether BTZ or CFZ combined with obatoclax (OBX), an antagonist for MCL-1 and a pan-BCL family inhibitor, could cause synergistic growth inhibition of SCLC cells. We showed that combined application of BTZ or CFZ with OBX caused synergistic growth inhibition of human SCLC cell lines (H82, H526, DMS79, H196, H1963, and H69) than single agent alone. Both BTZ-OBX and CFZ-OBX combinations displayed marked synergism on inducing apoptosis (similar to 50% increase vs BTZ or CFZ alone). A comprehensive proteomics analysis revealed that BTZ preferentially induced the expression of MCL-1, an antiapoptotic protein, in SCLC cells. Thus, proteasome inhibitor-OBX combinations could specifically induce massive growth inhibition and apoptosis in SCLC cells. Subsequent proteome-wide profiling analysis of activated transcription factors suggested that BTZ- or CFZ-induced MCL-1 upregulation was transcriptionally driven by FOXM1. In nude mice bearing in SCLC H82 xenografts, both BTZ-OBX, and CFZ-OBX combinations exhibited remarkable antitumor activities against SCLC tumors evidenced by significant reduction of tumor size and the proliferation marker Ki-67 signals in tumor tissues as compared with single agent alone. Thus, proteasome inhibitor-OBX combinations are worth immediate assessments for SCLC in clinical settings.
资助项目	National Natural Science Foundation of China[81672647] ; National Natural Science Foundation of China[81872438] ; National Natural Science Foundation of China[81502632] ; National Natural Science Foundation of China[81372214] ; National Natural Science Foundation of China[81972191] ; Natural Science Foundation of Anhui Province[1608085MH179] ; 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	ANTITUMOR-ACTIVITY ; PHASE-II ; CARFILZOMIB ; MCL-1 ; CARBOPLATIN ; ANTAGONIST ; BORTEZOMIB ; RESISTANCE ; ETOPOSIDE ; MESYLATE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000584385300001
资助机构	National Natural Science Foundation of China ; Natural Science Foundation of Anhui Province ; 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/334002/105120]
专题	中国科学院合肥物质科学研究院
通讯作者	Ding, Chen; Hong, Bo; Lin, Wen-chu
作者单位	1.Univ Sci & Technol China, Hefei 230036, Peoples R China 2.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China 3.Beijing Inst Life, Natl Ctr Prot Sci, Beijing Proteome Res Ctr, State Key Lab Prote,PHOENIX Ctr, Beijing 102206, Peoples R China 4.Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China 5.Fudan Univ, Inst Biomed Sci, State Key Lab Genet Engn, Human Phenome Inst,Sch Life Sci,Zhongshan Hosp, Shanghai 200433, Peoples R China 6.Henan Normal Univ, Coll Life Sci, State Key Lab Cell Differentiat & Regulat, Xinxiang 453007, Henan, Peoples R China 7.Zhengzhou Univ, Acad Med Sci, Zhengzhou 450052, Peoples R China 8.Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Peoples R China
推荐引用方式 GB/T 7714	Yin, Yan-ping,Shi, Wen-hao,Deng, Ke,et al. Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer[J]. ACTA PHARMACOLOGICA SINICA,2020.
APA	Yin, Yan-ping.,Shi, Wen-hao.,Deng, Ke.,Liu, Xiao-li.,Li, Hong.,...&Lin, Wen-chu.(2020).Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer.ACTA PHARMACOLOGICA SINICA.
MLA	Yin, Yan-ping,et al."Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer".ACTA PHARMACOLOGICA SINICA (2020).