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ZL-n-91, a specific Phosphodiesterase-4 inhibitor, suppresses the growth of triple-negative breast cancer

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Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that frequently develops resistance to chemotherapy. A new approach to treating TNBC is required to improve patient survival. Phosphodiesterase-4 (PDE4) is an enzyme that is predominantly involved in the modulation of intracellular signaling mediated by cAMP. Although the efficacy of PDE4 inhibitors in several human inflammatory diseases is well documented, their clinical utility has been limited by side effects, including nausea and emesis. Recently, PDE4 has been used as a potential therapeutic target for different cancer types. In the present study, we investigated the anticancer effects of a novel PDE4 inhibitor ZL-n-91 on TNBC and the underlying mechanism. We showed that ZL-n-91 inhibited the proliferation of TNBC cells, induced cell apoptosis, and caused cell cycle arrest. Western blot analysis showed that ZL-n-91 increased Bax level and reduced Bcl-2 expression. Furthermore, downregulation of the cell cycle-related proteins, such as CDK2, CDK4, cyclin D1, PCNA, p-RB, and ZL-n-91, significantly inhibited the transcription of DNA repair genes and triggered an intracellular DNA damage response. Moreover, ZL-n-91 prevented the growth of the transplanted MDA-MB-231 tumor xenograft in nude mice and increased the γ-H2AX expression. These data demonstrate the anticancer effects of ZL-n-91 on TNBC cells and suggest its potential use in anticancer therapy.

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All of the data generated or analyzed during this study are included in this manuscript.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2018YFA0800600); the National Natural Science Foundation of China (81630021); Key Research and Development Program of Guangdong Province for “Innovative drug creation” (2019B020201015); the Guangdong Innovative Research Team Program (2016ZT06Y432); the National Program on Key Basic Research Project of China (2013CB945202); the Startup R&D Funding of Guangdong University of Technology (50010102); and the GuangZhou Basic and Applied Basic Research Foundation (202102021117, 202102020159).

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Authors and Affiliations

  1. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China

    Longming Liang, Hansi Chen, Ping Mao, Yuyu Li, Lijun Xu, Yujie He, Yunping Mu, Allan Z. Zhao, Sujin Zhou Ph.D., Zhenggang Zhao Ph.D. & Fanghong Li M.D.

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  1. Longming Liang
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  2. Hansi Chen
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Contributions

Z.S.J, Z.Z.G, and L.F.H designed and supervised the study. L.L.M conducted the experiments, analyzed the data, and wrote the manuscript. C.H.S and M.P conducted the experiments and analyzed the data. L.Y.Y, X.L.J, H.Y.J, and M.Y.P assisted with the animal experiments. Z.Z.G and L.F.H conceived and organized the manuscript. Z.S.J and A.Z.Z reviewed and edited the manuscript.

Corresponding authors

Correspondence to Sujin Zhou Ph.D., Zhenggang Zhao Ph.D. or Fanghong Li M.D..

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Liang, L., Chen, H., Mao, P. et al. ZL-n-91, a specific Phosphodiesterase-4 inhibitor, suppresses the growth of triple-negative breast cancer. Invest New Drugs 40, 875–883 (2022). https://doi.org/10.1007/s10637-022-01258-y

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