title: Phosphodiesterase inhibitor, pentoxifylline enhances anticancer activity of histone deacetylase inhibitor, MS-275 in human breast cancer in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Ltd., Old Mahabalipuram Road, Sozhanganallur, Chennai 600119, Tamil Nadu, India; Jawaharlal Nehru Technological University Anantapur, Anantapur, 515 002 Andhra Pradesh, India. Electronic address: Saran.nithy@gmail.com.
authors.forename: Saranya
authors.initials: S
authors.lastname: Nidhyanandan
authors.affiliation: Department of Biomedical Science, College of Pharmacy, Shaqra University, Al-Dawadmi, Kingdom of Saudi Arabia.
authors.forename: Thippeswamy S
authors.initials: TS
authors.lastname: Boreddy
authors.affiliation: Jawaharlal Nehru Technological University Anantapur, Anantapur, 515 002 Andhra Pradesh, India.
authors.forename: Kothapalli B
authors.initials: KB
authors.lastname: Chandrasekhar
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Ltd., Old Mahabalipuram Road, Sozhanganallur, Chennai 600119, Tamil Nadu, India.
authors.forename: Neetinkumar D
authors.initials: ND
authors.lastname: Reddy
authors.affiliation: Department of Biology, Drug Discovery Research, Orchid Chemicals and Pharmaceuticals Ltd., Old Mahabalipuram Road, Sozhanganallur, Chennai 600119, Tamil Nadu, India.
authors.forename: Nagaraj M
authors.initials: NM
authors.lastname: Kulkarni
authors.affiliation: Foundation for Neglected Disease Research, Sir M Visvesvaraya Institute of Technology, International Airport Road, Yelahanka, Bangaluru 562157, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D061986:MCF-7 Cells; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; C118739:entinostat; D010431:Pentoxifylline
keywords: Apoptosis; HDAC; MS-275; PDE; Pentoxifylline; Xenograft