Enhanced anticancer efficacy of histone deacetyl inhibitor, suberoylanilide hydroxamic acid, in combination with a phosphodiesterase inhibitor, pentoxifylline, in human cancer cell lines and in-vivo tumor xenografts
| Autor: | Kottapalli B. Chandrasekhar, Kandasamy Karthikeyan, Shridhar Narayanan, Govindharajan Vijaykanth, B.S. Thippeswamy, Farhin R. Khan, Nagaraj M. Kulkarni, Neetinkumar D. Reddy, Jayaprakash Raghul, Saranya Nidhyanandan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cancer Research Phosphodiesterase Inhibitors Apoptosis Mice SCID Pharmacology Hydroxamic Acids Pentoxifylline Mice Random Allocation 0302 clinical medicine Neoplasms Antineoplastic Combined Chemotherapy Protocols Pharmacology (medical) media_common Vorinostat biology Neovascularization Pathologic Chemistry Histone deacetylase inhibitor Cell Cycle Drug Synergism Histone Oncology Biochemistry 030220 oncology & carcinogenesis MCF-7 Cells medicine.drug Drug medicine.drug_class media_common.quotation_subject Cell Growth Processes 03 medical and health sciences In vivo Cell Line Tumor medicine Human Umbilical Vein Endothelial Cells Animals Humans Phosphodiesterase inhibitor HCT116 Cells Xenograft Model Antitumor Assays Histone Deacetylase Inhibitors 030104 developmental biology Cell culture biology.protein |
| Zdroj: | Anti-cancer drugs. 28(9) |
| ISSN: | 1473-5741 |
| Popis: | Vorinostat [suberoylanilide hydroxamic acid (SAHA)], a histone deacetylase inhibitor, shows limited clinical activity against solid tumors when used alone. The methyl xanthine drug, pentoxifylline (PENT), has been described to have antitumor properties. The aim of this study was to look for the enhanced anticancer activities of both agents when used in combination at doses lower than their respective efficacy dose when used alone. We investigated the antitumor potential of this novel combination in vitro and in vivo. The combination index was assessed for these two drugs to look for synergistic antiproliferative activity against a broad spectrum of human cancer cell lines. Consistent additive to synergistic interactions were observed in HCT116 cells when PENT was combined with SAHA at all drug tested concentrations. The combination of SAHA and PENT induces chromatin condensation and apoptosis downstream of the pan histone deacetylase inhibition and phosphodiesterase regulation, leading to subsequent cell cycle arrest at their lower tested concentrations. Further, the ability of this combination to inhibit angiogenesis, both in vitro and in vivo, was examined and a significant inhibition in tube formation in HUVEC cells and neovascularization of Matrigel plug was observed. A significant inhibition in tumor growth was observed in severe combined immunodeficient mice bearing HCT116 (colon) and PC3 (prostate) human xenografts treated with SAHA (30 mg/kg, intraperitoneal) in combination with PENT (60 mg/kg, intraperitoneal), with no loss in body weight and 100% survival. In conclusion, these findings indicate the enhanced anticancer activity of SAHA in combination with PENT both in vitro and in vivo. |
| Databáze: | OpenAIRE |
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