Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A
| Autor: | Karen TenDyke, Roch Boivin, Hong Du, Sergei Agoulnik, Daniel Romo, Yuan Wang, Zhihong Chen, Lana Parent, Huiming Zhang, Nanding Zhao, Bruce A. Littlefield, Jue-lon Shie, Yimin Jiang, Natalie C. Twine, Lori Rudolph-Owen, Murray J. Towle, Joanne Marsh, Qunli Xu, Junke Liu, Galina Kuznetsov |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Mice Nude Antineoplastic Agents Mice SCID Pharmacology Biology Article chemistry.chemical_compound Mice In vivo Cell Line Tumor Neoplasms Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Cytotoxicity Cell Proliferation Natural product Cell growth Cell Cycle Cell cycle Xenograft Model Antitumor Assays In vitro Thiazoles Oncology chemistry Paclitaxel Biochemistry Cell culture Drug Resistance Neoplasm Epoxy Compounds Female Macrolides |
| Zdroj: | Molecular cancer therapeutics. 8(5) |
| ISSN: | 1538-8514 |
| Popis: | We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDA-PatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.[Mol Cancer Ther 2009;8(5):1250–60] |
| Databáze: | OpenAIRE |
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