Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A

• Published in: Molecular cancer therapeutics 2009-05, Vol.8 (5), p.1250-1260
• Main Authors: Kuznetsov, Galina, Xu, Qunli, Rudolph-Owen, Lori, Tendyke, Karen, Liu, Junke, Towle, Murray, Zhao, Nanding, Marsh, Joanne, Agoulnik, Sergei, Twine, Natalie, Parent, Lana, Chen, Zhihong, Shie, Jue-Lon, Jiang, Yimin, Zhang, Huiming, Du, Hong, Boivin, Roch, Wang, Yuan, Romo, Daniel, Littlefield, Bruce A
• Format: Article
• Language: English
• Subjects: Animals; anticancer; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; DMDA-PatA; DNA polymerase; DNA synthesis; Drug Resistance, Neoplasm - drug effects; Epoxy Compounds - chemistry; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Female; Humans; Macrolides - chemistry; Macrolides - pharmacology; Macrolides - therapeutic use; Mice; Mice, Nude; Mice, SCID; natural product; Neoplasms - drug therapy; Neoplasms - pathology; Thiazoles - chemistry; Thiazoles - pharmacology; Thiazoles - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-1026

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]