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Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells

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Abstract

Studies were performed to determine the influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to Adriamycin (doxorubicin) in four human breast tumor cell lines and one murine breast tumor line. Sildenafil did not interfere with the effectiveness of Adriamycin in any of the cell lines tested. Sildenafil also failed to protect MDA-MB231 cells against the cytotoxicity of cisplatin, taxol or camptothecin. Sildenafil enhanced sensitivity to Adriamycin markedly in the p53 mutant MDA-MB231 and p53 null MCF-7/E6 cells and moderately in the MCF-7/caspase 3 and 4T1 cell lines. In the MDA-MB231 cells, sildenafil increased the extent of DNA damage induced by Adriamycin as well as the extent of apoptotic cell death. Sildenafil did not influence sensitivity to Adriamycin in bone marrow cells or macrophages. In an immunocompetent model of breast cancer (4T1 mammary carcinoma in Balb/c mice), sildenafil did not attenuate the antitumor effects of Adriamycin; furthermore, the combination of sildenafil with Adriamycin was no more toxic to the animals than Adriamycin alone. Given that sildenafil has been shown to have the potential to protect the heart against the toxicity of Adriamycin, these studies suggest that the inclusion of sildenafil with conventional chemotherapeutic protocols involving Adriamycin (and possibly cisplatin, camptothecin and/or paclitaxel) should not compromise the antitumor effectiveness of these drugs nor enhance their toxicity to the patient.

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Notes

  1. In a separate study, where the mice received a second dose of Adriamycin of 5 mg/kg, we also observed that sildenafil did not interfere with the antitumor actions of Adriamycin nor exacerbate the weight loss (data not shown). Tumor-bearing mice that were not treated with drug showed no weight loss and essentially maintained their weight after an initial slight weight gain (data not shown).

  2. It should be noted that it cannot be readily determined whether the reactive species measured reflect peroxide released during apoptosis or residual ROS generated directly from Adriamycin metabolism within the cell.

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Acknowledgments

This study was supported by the U.S. Army Medical Research and Material Command Grant # W81XWH-06-1-0360. The sildenafil was generously provided by Pfizer, Inc. We thank Dr. Matthew J. Smith for assistance with preparation of the macrophages.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Massey Cancer Center, 401 College St., Richmond, VA, 23298, USA

    Xu Di & David A. Gewirtz

  2. Department of Biostatistics, Virginia Commonwealth University, 730 E. Broad St., Richmond, VA, 23298, USA

    Chris Gennings

  3. Department of Surgery, Virginia Commonwealth University, Massey Cancer Center, 401 College St., Richmond, VA, 23298, USA

    Harry D. Bear & Laura J. Graham

  4. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Strauss Research Laboratories, 527 N. 12th St., Richmond, VA, 23298, USA

    Christopher M. Sheth & Kimber L. White Jr.

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  1. Xu Di
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  2. Chris Gennings
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  3. Harry D. Bear
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  4. Laura J. Graham
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  7. David A. Gewirtz
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Correspondence to David A. Gewirtz.

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Di, X., Gennings, C., Bear, H.D. et al. Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res Treat 124, 349–360 (2010). https://doi.org/10.1007/s10549-010-0765-7

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  • DOI: https://doi.org/10.1007/s10549-010-0765-7

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