Translational Therapeutics

Compensatory combination of romidepsin with gemcitabine and cisplatin to effectively and safely control urothelial carcinoma

Subjects

Abstract

Background

Human urothelial carcinoma (UC) has a high tendency to recur and progress to life-threatening advanced diseases. Advanced therapeutic regimens are needed to control UC development and recurrence.

Methods

We pursued in vitro and in vivo studies to understand the ability of a triple combination of gemcitabine, romidepsin, and cisplatin (Gem+Rom+Cis) to modulate signalling pathways, cell death, drug resistance, and tumour development.

Results

Our studies verified the ability of Gem+Rom+Cis to synergistically induce apoptotic cell death and reduce drug resistance in various UC cells. The ERK pathway and reactive oxygen species (ROS) played essential roles in mediating Gem+Rom+Cis-induced caspase activation, DNA oxidation and damage, glutathione reduction, and unfolded protein response. Gem+Rom+Cis preferentially induced death and reduced drug resistance in oncogenic H-Ras-expressing UC vs. counterpart cells that was associated with transcriptomic profiles related to ROS, cell death, and drug resistance. Our studies also verified the efficacy and safety of the Gem plus Rom+Cis regimen in controlling UC cell-derived xenograft tumour development and resistance.

Conclusions

More than 80% of UCs are associated with aberrant Ras-ERK pathway. Thus the compensatory combination of Rom with Gem and Cis should be seriously considered as an advanced regimen for treating advanced UCs, especially Ras-ERK-activated UCs.

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Fig. 1: ROS- and ERK-Nox-dependent cell death synergistically induced by combined Rom, Cis, and Gem.
Fig. 2: Preferential induction of cell death and suppression of drug resistance by Rom+Cis+Gem in J82-Ras vs. J82 cells.
Fig. 3: Transcriptomic profiles associated with Rom+Cis+Gem.
Fig. 4: BiP contributed to cell death induced by Rom+Cis+Gem.
Fig. 5: Efficacy of the Gem plus Rom+Cis regimen in controlling J82-Ras CDXs.
Fig. 6: Efficacy of Gem plus Rom+Cis in controlling T24 CDX.

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Acknowledgements

We are grateful to Dr. L. Pluchino and Ms. D.J. Trent for technical supports, Dr. A. Odoi for statistical consultation, and Ms. A. Hand for textual editing of the manuscript.

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Contributions

H.-C.R.W. designed the experiments. P.P. performed in vitro experiments. Y.H. contributed to establishing J82-BiPs and J82-shBiPs cell lines. P.P., Y.H., S.W., and J.W. contributed to in vivo experiments. T.H., T.-H.W., and C.-L.T. performed computational data analysis. R.D. contributed to histological analysis.

Corresponding author

Correspondence to Hwa-Chain Robert Wang.

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Ethics approval and consent to participate

All animal procedures were approved by the University of Tennessee Animal Care and Use Committee and were in accordance with the NIH Guide for the Care and Use of Laboratory Animals.

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All the data related to this study are included in this article and its supplementary file.

Competing interests

The authors declare no competing interests.

Funding information

This study was supported by the National Institutes of Health [CA177834 to H.-C.R.W.] and the University of Tennessee, Center of Excellence in Livestock Diseases and Human Health [to H.-C.R.W.].

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Pattarawat, P., Hong, T., Wallace, S. et al. Compensatory combination of romidepsin with gemcitabine and cisplatin to effectively and safely control urothelial carcinoma. Br J Cancer 123, 226–239 (2020). https://doi.org/10.1038/s41416-020-0877-8

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