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Formulation of a triple combination gemcitabine plus romidepsin + cisplatin regimen to efficaciously and safely control triple-negative breast cancer tumor development

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Abstract

Purpose

Triple-negative breast cancer (TNBC) is an aggressive, lethal, and heterogeneous subtype of breast cancers, tending to have lower 5-year survival rates than other BC subtypes in response to conventional chemotherapies. This study’s aim was to identify advanced regimens to effectively control TNBC tumor development.

Methods

We investigated the combination of the DNA synthesis inhibitor gemcitabine, the DNA-damaging agent cisplatin, and the histone deacetylase inhibitor romidepsin to control a variety of breast cells in vitro. We studied the toxicity of drug doses and administration schedules to determine tolerable combination regimens in immune-deficient nude and -competent BALB/c mice. We then studied the efficacy of tolerable regimens in controlling TNBC cell-derived xenograft development in nude mice. By reducing clinically equivalent doses of each agent in combination, we formulated tolerable regimens in animals. We verified that the tolerable triple combination gemcitabine plus romidepsin + cisplatin regimen more efficacious than double combination regimens in controlling xenograft tumor development in nude mice.

Results

A triple combination of gemcitabine + romidepsin + cisplatin synergistically induced death of the TNBC M.D. Anderson-Metastatic Breast cancer (MDA-MB) 231 and MDA-MB468, as well as Michigan Cancer Foundation (MCF) 7, MCF10A, and MCF10A-Ras cells. Cell death induced by gemcitabine + romidepsin + cisplatin was in a reactive oxygen species-dependent manner.

Conclusion

Considering the high costs for developing a new anticancer agent, we used the FDA-approved drugs gemcitabine, romidepsin (is approved for T-cell lymphoma and is under clinical trial for TNBC), and cisplatin to economically formulate an efficacious and safe combination regimen. The highly efficacious gemcitabine plus romidepsin + cisplatin regimen should be poised for efficient translation into clinical trials, ultimately contributing to reduced mortality and improved quality of life for TNBC patients.

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Abbreviations

BC:

Breast cancer

CDX:

Cell-derived xenograft

CI:

Combination index

Cis:

Cisplatin

CM–H2DCF–DA:

Chloromethyl–dichlorodihydrofluorescein–diacetate

DMEM:

Dulbecco's Modified Eagle Medium

DMSO:

Dimethyl sulfoxide

ER:

Estrogen receptor

Gem:

Gemcitabine

FITC:

Fluorescein isothiocyanate

HER:

Human epidermal growth factor receptor

IC:

Inhibitory concentration

MCF:

Michigan Cancer Foundation

MDA-MB:

M.D. Anderson-Metastatic Breast cancer

MTD:

Maximum tolerable dose

MTT:

Methyl thiazolyl tetrazolium

NAC:

N-Acetylcysteine

PARP:

Poly(ADP-ribose) polymerase

PBS:

Phosphate-buffered saline

Rom:

Romidepsin

ROS:

Reactive oxygen species

TNBC:

Triple-negative breast cancer

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Acknowledgements

We are grateful to Ms. DJ Trent for technical support in flow cytometric analysis and Ms. Amanda Hand for textual editing of the manuscript. 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 (H-C.R.W.).

Funding

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

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Authors and Affiliations

  1. Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN, 37996, USA

    Pawat Pattarawat, Shelby Wallace, Bianca Pfisterer, Agricola Odoi & Hwa-Chain Robert Wang

  2. UT-ORNL Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN, 37996, USA

    Pawat Pattarawat & Hwa-Chain Robert Wang

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  1. Pawat Pattarawat
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Corresponding author

Correspondence to Hwa-Chain Robert Wang.

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The Author Pawat Pattarawat declares that he has no conflict of interest. The Author Shelby Wallace declares that she has no conflict of interest. The Author Bianca Pfisterer declares that she has no conflict of interest. The Author Agricola Odoi declares that he has no conflict of interest. The Author Hwa-Chain Robert Wang declares that he has no conflict of interest.

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All applicable national (the NIH Guide for the Care and Use of Laboratory Animals) and institutional (the University of Tennessee Animal Care and Use Committee) guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Pattarawat, P., Wallace, S., Pfisterer, B. et al. Formulation of a triple combination gemcitabine plus romidepsin + cisplatin regimen to efficaciously and safely control triple-negative breast cancer tumor development. Cancer Chemother Pharmacol 85, 141–152 (2020). https://doi.org/10.1007/s00280-019-04013-y

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