Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells
Fariba Hassanvand1, Tannaz Mohammadi2, Negar Ayoubzadeh3, Atieh Tavakoli4, Naiemeh Hassanzadeh5, Nafiseh Sadat Sanikhani6, Ali Ipakchi Azimi7, Hamid Reza Mirzaei8, Mehdi Khodamoradi9, Kazem Abbaszadeh Goudarzi10, Hossein Pourghadamyari11, Mohamad Ali Zaimy12
1 Department of Biological Sciences and Biotechnology, University of Kurdistan, Iran
2 Molecular and Cellular Biology Department, Islamic Azad University Tehran Medical Branch, Tehran, Iran
3 Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
4 Department of Molecular Genetics, Islamic Azad University, Damghan, Iran
5 Department of Biology, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
6 Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
7 Department of Medical Laboratory Science, Medical Science Faculty Babol Islamic Azad University, Babol, Iran
8 Department of Medical Immunology, Tehran University of Medical Sciences, School of Medicine, Tehran, Iran
9 Substance Abuse Prevention Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
10 Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
11 Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
12 Department of Medical Genetic, Ilam University of Medical Sciences, Ilam, Iran
Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman
Source of Support: None, Conflict of Interest: None
Introduction: Cyclic nucleotide phosphodiesterase (PDE) enzymes are a large superfamily of enzymes that catalyze the conversion reaction of cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) to AMP and GMP, respectively. In some cancer cells, PDE-5 has been shown to be overexpressed in multiple human carcinomas. It seems that the inhibition of PDE-5 may has anticancer effects. Cisplatin is one of the prevalent chemo-agents to treat solid tumors. However, its clinical usefulness is hindered by dose-limiting toxicities, especially on the kidneys (nephrotoxicity) and ears (ototoxicity). In this study, the antitumor activity of the sildenafil as a PDE-5 inhibitor alone and in combination with cisplatin on human mammary adenocarcinomas and MCF-7 and MDA-MB-468 was assessed.
Materials and Methods: Sildenafil as PDE type 5 (PDE5) inhibitor is the drugs that we combined with the cisplatin (chemotherapeutic agent), in vitro. Human mammary adenocarcinomas and MCF-7 and MDA-MB-468 cell lines were cultured in standard conditions. At time point, following 24 h and 48 h incubation, the cell lines were treated by cisplatin in the presence/absence of sildenafil. Cell viability, apoptosis, and reactive oxygen species (ROS) were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, real-time polymerase chain reaction, and Western blot; and fluorimetric methods, respectively. Statistical analysis was performed using SPSS software SPSS (SPSS Inc., Chicago, IL, USA).
Results: In MCF-7 cell line, following 24 h incubation, combinations of sildenafil with cisplatin (P < 0.001) showed decreased cell viability when compared to sildenafil and cisplatin alone. Moreover in MDA-MB-468 cell line, following 24 h incubation, data did not show any significant changes on cell viability when treated with cisplatin, in the presence or absence of sildenafil. However, following 48 h incubation, combinations of cisplatin with sildenafil (P < 0.001) were showed decreased cell viability when compared to cisplatin and sildenafil alone in both MCF-7 and MDA-MB-468 cell lines. Concerning the ROS production and apoptosis, data showed that both processes increase significantly in the presence of the sildenafil in comparison absent it.
Conclusion: Our data showed that the combination of sildenafil with cisplatin can improve cell toxicity and anticancer effect of cisplatin. And also sildenafil as a PDE-5 inhibitor could be used as additive treatment in combination with cisplatin to make a reduction in cisplatin dosage and its side effects.