title: Synergistic inhibition of tumor growth and metastasis by combined treatment with TNP-470 and docetaxel in a human prostate cancer PC-3 model.
abstract: TNP-470, a potent inhibitor of angiogenesis, was reported to synergistically enhance the antitumor effects of cytotoxic agents. The objective of this study was to evaluate the effectiveness of combined treatment with TNP-470 and docetaxel both in vitro and in vivo using androgen-independent human prostate cancer PC-3 cells. The in vitro growth-inhibitory and apoptotic effects of docetaxel and/or TNP-470 on PC-3 cells were assessed using MTT and TUNEL assays. The combined effect of docetaxel and TNP-470 therapy after subcutaneous and orthotopic injection of PC-3 cells into athymic nude mice was evaluated. In vivo effects of this combined regimen on PC-3 tumors were analyzed by the TUNEL assay and immunohistochemical staining of CD31 to quantify microvessel density (MVD). Combined treatment with TNP-470 and docetaxel synergistically inhibited PC-3 cell growth in vitro through the enhanced induction of apoptotic cell death compared with treatment with either agent alone, a result explained, at least in part, by the down-regulation as well as phosphorylation of potential anti-apoptotic genes, Bcl-2 and Bcl-XL. Combined treatment with TNP-470 and docetaxel synergistically suppressed subcutaneous PC-3 tumor growth compared with treatment with either agent alone. Furthermore, this combined regimen significantly inhibited orthotopic PC-3 tumor growth and reduced the incidence of lymph node metastasis. Immunohistochemical analysis of the subcutaneous tumor after each treatment demonstrated that administration of docetaxel as well as TNP-470 significantly induced apoptotic cell death; in contrast, a significant reduction in MVD was observed only after TNP-470. These findings suggest that docetaxel and TNP-470 act synergistically to inhibit PC-3 tumor growth and metastasis, by enhancing apoptosis and suppressing angiogenesis.
authors.affiliation: The Prostate Centre, Jack Bell Research Centre, Vancouver, British Columbia V6H 3Z6, Canada. mmuramak@vanhosp.bc.ca
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Muramaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyake
authors.forename: Isao
authors.initials: I
authors.lastname: Hara
authors.forename: Sadao
authors.initials: S
authors.lastname: Kamidono
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003510:Cyclohexanes; D000077143:Docetaxel; D004347:Drug Interactions; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011471:Prostatic Neoplasms / Q000473:pathology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D043823:Taxoids; D000077143:Docetaxel; D000077609:O-(Chloroacetylcarbamoyl)fumagillol