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

Guo-zhen Cao1,2,3, Li-ying Ma1,2,3, Zong-hui Zhang1,4, Xiao-lin Wang2, Jing-han Hua1,2,3, Jia-hui Zhang1,2,3, Yang Lv1,2,3, Shao-bo Zhang1,4, Jian Ou5, Wen-chu Lin1,2,3
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 230036, 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
4 School of Basic Medicine, Anhui Medical University, Hefei 230032, China
5 Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215002, China
Correspondence to: Wen-chu Lin: wenchu@hmfl.ac.cn,
DOI: 10.1038/s41401-022-00994-4
Received: 25 April 2022
Accepted: 2 September 2022
Advance online: 17 October 2022

Abstract

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 G2/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.
Keywords: small-cell lung cancer; H3.3; PARP1; PARP inhibitor; darinaparsin; combination treatment

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