PMID- 33342806 OWN - NLM STAT- MEDLINE DCOM- 20210823 LR - 20220419 IS - 1998-4138 (Electronic) IS - 1998-4138 (Linking) VI - 16 IP - 6 DP - 2020 Oct-Dec TI - Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells. PG - 1412-1418 LID - 10.4103/jcrt.JCRT_675_19 [doi] AB - 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. FAU - Hassanvand, Fariba AU - Hassanvand F AD - Department of Biological Sciences and Biotechnology, University of Kurdistan, Iran. FAU - Mohammadi, Tannaz AU - Mohammadi T AD - Molecular and Cellular Biology Department, Islamic Azad University Tehran Medical Branch, Tehran, Iran. FAU - Ayoubzadeh, Negar AU - Ayoubzadeh N AD - Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran. FAU - Tavakoli, Atieh AU - Tavakoli A AD - Department of Molecular Genetics, Islamic Azad University, Damghan, Iran. FAU - Hassanzadeh, Naiemeh AU - Hassanzadeh N AD - Department of Biology, Tehran Medical Branch, Islamic Azad University, Tehran, Iran. FAU - Sanikhani, Nafiseh Sadat AU - Sanikhani NS AD - Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. FAU - Azimi, Ali Ipakchi AU - Azimi AI AD - Department of Medical Laboratory Science, Medical Science Faculty Babol Islamic Azad University, Babol, Iran. FAU - Mirzaei, Hamid Reza AU - Mirzaei HR AD - Department of Medical Immunology, Tehran University of Medical Sciences, School of Medicine, Tehran, Iran. FAU - Khodamoradi, Mehdi AU - Khodamoradi M AD - Substance Abuse Prevention Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. FAU - Goudarzi, Kazem Abbaszadeh AU - Goudarzi KA AD - Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran. FAU - Pourghadamyari, Hossein AU - Pourghadamyari H AD - Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran. FAU - Zaimy, Mohamad Ali AU - Zaimy MA AD - Department of Medical Genetic, Ilam University of Medical Sciences, Ilam, Iran. LA - eng PT - Journal Article PL - India TA - J Cancer Res Ther JT - Journal of cancer research and therapeutics JID - 101249598 RN - 0 (Phosphodiesterase 5 Inhibitors) RN - BW9B0ZE037 (Sildenafil Citrate) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Adenocarcinoma/*drug therapy/pathology MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use MH - Apoptosis/drug effects MH - Breast Neoplasms/*drug therapy/pathology MH - Cisplatin/*pharmacology/therapeutic use MH - Drug Screening Assays, Antitumor MH - Drug Synergism MH - Female MH - Humans MH - MCF-7 Cells MH - Phosphodiesterase 5 Inhibitors/pharmacology/therapeutic use MH - Sildenafil Citrate/*pharmacology/therapeutic use OTO - NOTNLM OT - Antitumor activity OT - apoptosis OT - breast cancer OT - cisplatin OT - sildenafil COIS- None EDAT- 2020/12/22 06:00 MHDA- 2021/08/24 06:00 CRDT- 2020/12/21 06:01 PHST- 2020/12/21 06:01 [entrez] PHST- 2020/12/22 06:00 [pubmed] PHST- 2021/08/24 06:00 [medline] AID - JCanResTher_2020_16_6_1412_299888 [pii] AID - 10.4103/jcrt.JCRT_675_19 [doi] PST - ppublish SO - J Cancer Res Ther. 2020 Oct-Dec;16(6):1412-1418. doi: 10.4103/jcrt.JCRT_675_19.