Phosphodiesterase inhibitor, pentoxifylline enhances anticancer activity of histone deacetylase inhibitor, MS-275 in human breast cancer in vitro and in vivo.
MS-275, a histone deacetylase inhibitor (HDACi), is undergoing clinical trials for treatment of various cancers. Pentoxifylline, a nonselective phosphodiesterase (PDE) inhibitor, has been shown to increase the effectiveness of antitumor chemotherapy. In the present study, the potential anti-cancer activity of MS-275 in combination with pentoxifylline in panel of cell lines and human breast cancer xenograft model were examined. A Panel of cancer cell lines were treated with MS-275 and pentoxifylline to determine their impact on cellular proliferation, cell cycle regulation, apoptosis, anti-angiogenesis. The in vivo activities of MS-275 and pentoxifylline were assessed in a Matrigel plug angiogenesis model and human breast cancer (MDA-MB-231) xenograft model. Combination of MS-275 with pentoxifylline showed enhanced anti-proliferative activity in a panel of cancer cell lines (HCT 116, MCF-7, PC3 and MDA-MB-231). Apoptotic studies performed using, Hoechst staining and cell cycle analysis reveal that this combination at the lower concentrations induces apoptosis downstream of the HDAC inhibition and PDE regulation. Further, combination showed enhanced antiangiogenic activity in Matrigel tube formation assay using HUVECs and in Matrigel plug assay in vivo. A significant inhibition (P<0.001) of tumor growth was observed in mice bearing MDA-MB-231 breast cancer xenograft treated with the combination of MS-275 (5mg/kg p.o.) and pentoxifylline (60 mg/kg i.p.) than treatments alone, without much signs of toxicity. Taken together, our study demonstrated enhanced anticancer activity of MS-275 and pentoxifylline combination both in vitro and in vivo with reduced toxicity. However, further studies are required to understand the mechanism for this combination effect.
['Nidhyanandan|Saranya|S|', 'Boreddy|Thippeswamy S|TS|', 'Chandrasekhar|Kothapalli B|KB|', 'Reddy|Neetinkumar D|ND|', 'Kulkarni|Nagaraj M|NM|', 'Narayanan|Shridhar|S|']
D020533:Angiogenesis Inhibitors D000818:Animals D000971:Antineoplastic Combined Chemotherapy Protocols D017209:Apoptosis D001549:Benzamides D001943:Breast Neoplasms D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D004357:Drug Synergism D005260:Female D045325:HCT116 Cells D056572:Histone Deacetylase Inhibitors D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D061986:MCF-7 Cells D016513:Mice, SCID D009389:Neovascularization, Pathologic D010431:Pentoxifylline D010726:Phosphodiesterase Inhibitors D011725:Pyridines D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
Pentoxifylline MS-275 PDE Xenograft Apoptosis HDAC