Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors

doi:10.1038/s41401-022-00994-4

	Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors
	Cao, Guo-Zhen 1,2,3; Ma, Li-Ying 1,2,3; Zhang, Zong-Hui 1,4; Wang, Xiao-Lin 2; Hua, Jing-Han 1,2,3; Zhang, Jia-Hui 1,2,3; Lv, Yang 1,2,3; Zhang, Shao-Bo 1,4; Ou, Jian 5; Lin, Wen-Chu 1,2,3
刊名	ACTA PHARMACOLOGICA SINICA
	2022-10-17
关键词	small-cell lung cancer H3 3 PARP1 PARP inhibitor darinaparsin combination treatment
ISSN号	1671-4083
DOI	10.1038/s41401-022-00994-4
通讯作者	Lin, Wen-Chu(wenchu@hmfl.ac.cn)
英文摘要	Small-cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine carcinoma of the lung associated with early metastasis and an exceptionally poor prognosis. Little progress has been made in developing efficacious targeted therapy for this recalcitrant disease. Herein, we showed that H3.3, encoded by two genes (H3F3A and H3F3B), was prominently overexpressed in SCLC. Darinaparsin (ZIO-101), a derivative of arsenic trioxide, dose- and time-dependently inhibited the viability of SCLC cells in an H3.3-dependent manner. More importantly, ZIO-101 treatment resulted in substantial accumulation of H3.3 and PARP1 besides induction of G(2)/M cell cycle arrest and apoptosis in SCLC cells. Through integrative analysis of the RNA-seq data from Cancer Cell Line Encyclopedia dataset, JNCI and Genomics of Drug Sensitivity in Cancer 2 datasets, we found that H3F3A expression was negatively correlated with the IC50 values of PARP inhibitors (PARPi). Furthermore, co-targeting H3.3 and PARP1 by ZIO-101 and BMN673/olaparib achieved synergistic growth inhibition against SCLC in vitro and in vivo. In conclusion, it is feasible to target H3.3 by ZIO-101 to potentiate the response rate of PARPi in SCLC patients.
资助项目	National Natural Science Foundation of China (China)[81972191] ; National Natural Science Foundation of China (China)[81672647] ; High Magnetic Field Laboratory of Anhui Province
WOS关键词	HISTONE VARIANT H3.3 ; TUMOR ; MUTATIONS ; DISEASE ; TARGETS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000869326100002
资助机构	National Natural Science Foundation of China (China) ; High Magnetic Field Laboratory of Anhui Province
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/129470]
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, High Magnet Field Lab, Hefei 230031, Peoples R China 2.Univ Sci & Technol China, Hefei 230036, Peoples R China 3.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China 4.Anhui Med Univ, Sch Basic Med, Hefei 230032, Peoples R China 5.Nanjing Med Univ, Suzhou Municipal Hosp, Ctr Reprod & Genet, Affiliated Suzhou Hosp, Suzhou 215002, Peoples R China
推荐引用方式 GB/T 7714	Cao, Guo-Zhen,Ma, Li-Ying,Zhang, Zong-Hui,et al. Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2022.
APA	Cao, Guo-Zhen.,Ma, Li-Ying.,Zhang, Zong-Hui.,Wang, Xiao-Lin.,Hua, Jing-Han.,...&Lin, Wen-Chu.(2022).Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors.ACTA PHARMACOLOGICA SINICA.
MLA	Cao, Guo-Zhen,et al."Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors".ACTA PHARMACOLOGICA SINICA (2022).