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

A Correction to this article was published on 13 November 2022

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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.

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Fig. 1: H3.3 is highly expressed in SCLC.
Fig. 2: ZIO-101 has an inhibitory effect on SCLC cells by targeting H3.3.
Fig. 3: Treatment with ZIO-101 induces cell cycle arrest and accumulation of H3.3 in SCLC.
Fig. 4: H3.3 expression positively correlates with the sensitivity of common chemotherapeutic drugs in SCLC.
Fig. 5: ZIO-101 markedly induces PARP1 expression in SCLC.
Fig. 6: Combined therapeutic effects of ZIO-101 and PARP inhibitors in vitro.
Fig. 7: Dual inhibitions of H3.3 and PARP are synergistic in vivo.

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Acknowledgements

The present study was supported by the National Natural Science Foundation of China (No. 81972191 and No. 81672647, China), and a portion of this work was supported by the High Magnetic Field Laboratory of Anhui Province.

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GZC and WCL conceived and designed the project. GZC, LYM, ZHZ, and JHZ performed most experiments and interpreted the data. YL, JHH, and SBZ performed part of in vivo experiments. GZC, XLW, and JO analyzed the data and prepared the figures and manuscript draft. WCL revised the manuscript. All authors have read and approved the manuscript.

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Correspondence to Wen-chu Lin.

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The original online version of this article was revised: After check of our published article entitled “Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors” in Acta Pharmacologica Sinica, we found that there were misspellings in Fig. 2, Fig. 6, Supplementary Fig. S2 and Supplementary Fig. S5. FTIC-A in these figures need to be modified to FITC-A. In addition, Fig.S1a and Fig.S5a should be changed to Fig.S1 and Fig.S5 in the text and the “a” should be deleted in the supplementary figures Fig.S1 and Fig.S5 and corresponding figure legends.

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Cao, Gz., Ma, Ly., Zhang, Zh. et al. Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00994-4

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Keywords

  • small-cell lung cancer
  • H3.3
  • PARP1
  • PARP inhibitor
  • darinaparsin
  • combination treatment

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