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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2010

01-11-2010 | Preclinical study

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

Authors: Xu Di, Chris Gennings, Harry D. Bear, Laura J. Graham, Christopher M. Sheth, Kimber L. White Jr., David A. Gewirtz

Published in: Breast Cancer Research and Treatment | Issue 2/2010

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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.
Appendix
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Footnotes
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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Metadata
Title
Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells
Authors
Xu Di
Chris Gennings
Harry D. Bear
Laura J. Graham
Christopher M. Sheth
Kimber L. White Jr.
David A. Gewirtz
Publication date
01-11-2010
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2010
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-010-0765-7

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