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Romidepsin and tamoxifen cooperatively induce senescence of pancreatic cancer cells through downregulation of FOXM1 expression and induction of reactive oxygen species/lipid peroxidation

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Abstract

Background

Although improvement has been made in therapeutic strategies against pancreatic carcinoma, overall survival has not significantly enhanced over the past decade. Thus, the establishment of better therapeutic regimens remains a high priority.

Methods

Pancreatic cancer cell lines were incubated with romidepsin, an inhibitor of histone deacetylase, and tamoxifen, and their effects on cell growth, signaling and gene expression were analyzed. Xenografts of human pancreatic cancer CFPAC1 cells were medicated with romidepsin and tamoxifen to evaluate their effects on tumor growth.

Results

The inhibition of the growth of pancreatic cancer cells induced by romidepsin and tamoxifen was effectively reduced by N-acetyl cysteine and α-tocopherol, respectively. The combined treatment greatly induced reactive oxygen species production and mitochondrial lipid peroxidation, and these effects were prevented by N-acetyl cysteine and α-tocopherol. Tamoxifen enhanced romidepsin-induced cell senescence. FOXM1 expression was markedly downregulated in pancreatic cancer cells treated with romidepsin, and tamoxifen further reduced FOXM1 expression in cells treated with romidepsin. Siomycin A, an inhibitor of FOXM1, induced senescence in pancreatic cancer cells. Similar results were obtained in knockdown of FOXM1 expression by siRNA.

Conclusion

Since FOXM1 is used as a prognostic marker and therapeutic target for pancreatic cancer, a combination of the clinically available drugs romidepsin and tamoxifen might be considered for the treatment of patients with pancreatic cancer.

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Data availability

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

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Acknowledgements

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Funding

This study was supported in part by a grant from the Shimane University ‘SUIGAN’ project.

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Authors and Affiliations

  1. Innovative Cancer Center, Shimane University, Izumo, Shimane, 693-8501, Japan

    Noriko Okuni, Yoshio Honma & Kenji Tamura

  2. Department of Biochemistry, Faculty of Medicine, Shimane University, Izumo, Shimane, 693-8501, Japan

    Yoshio Honma & Takeshi Urano

Authors
  1. Noriko Okuni
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  2. Yoshio Honma
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  3. Takeshi Urano
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  4. Kenji Tamura
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Contributions

All authors contributed to the manuscript as follows: Conceptualization, NO, YH, TU and KT; methodology, NO, YH and TU; investigation, NO and YH; writing of original draft, NO and YH; writing, revision and editing, YH, TU and KT; funding and supervision, TU and KT. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Yoshio Honma.

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The authors declare that they have no competing interests.

Ethical approval

All animal experiments were approved by the Ethics Committee of Shimane University (Approval No. IZ2-110) and were conducted in accordance with the Japanese laws associated with animal experiments, the institutional regulations of Shimane University and the Science Council of Japan guidelines for proper conduct of animal experiments.

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Okuni, N., Honma, Y., Urano, T. et al. Romidepsin and tamoxifen cooperatively induce senescence of pancreatic cancer cells through downregulation of FOXM1 expression and induction of reactive oxygen species/lipid peroxidation. Mol Biol Rep 49, 3519–3529 (2022). https://doi.org/10.1007/s11033-022-07192-9

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  • DOI: https://doi.org/10.1007/s11033-022-07192-9

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