title: Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis.
abstract: Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic, antiproliferative, and apoptotic activities of sildenafil.
authors.affiliation: Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6 October City, Egypt.
authors.forename: Mona Mohamed
authors.initials: MM
authors.lastname: El-Naa
authors.affiliation: Preparatory Year College, University of Hail, Hail, Kingdom of Saudi Arabia; Faculty of Biotechnology, October University for Modern Science and Arts (MSA), 6 October City, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Othman
authors.affiliation: Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt; College of Medicine, Princess Nora Bint Abdulrahman University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Sheren
authors.initials: S
authors.lastname: Younes
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D051379:Mice; D009336:Necrosis; D009389:Neovascularization, Pathologic; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D000068677:Sildenafil Citrate; D002945:Cisplatin
keywords: angiogenesis; apoptosis; breast cancer; phosphodiesterase-5; proliferation; sildenafil