Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells.
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.
Di
Xu
X
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Massey Cancer Center, 401 College St., Richmond, VA 23298, USA.
Gennings
Chris
C
Bear
Harry D
HD
Graham
Laura J
LJ
Sheth
Christopher M
CM
White
Kimber L
KL
Gewirtz
David A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D011687:Purines / Q000494:pharmacology / Q000633:toxicity; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D000068677:Sildenafil Citrate; D053148:Caspase 3; D017239:Paclitaxel; D002945:Cisplatin; D002166:Camptothecin