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

Abstract

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.

• Authors: Galina Kuznetsov, Qunli Xu, Lori Rudolph-Owen, Karen Tendyke, Junke Liu, Murray Towle, Nanding Zhao, Joanne Marsh, Sergei Agoulnik, Natalie Twine, Lana Parent, Zhihong Chen, Jue-Lon Shie, Yimin Jiang, Huiming Zhang, Hong Du, Roch Boivin, Yuan Wang, Daniel Romo, Bruce A Littlefield
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 5 Pg. 1250-60 (May 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19417157 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Epoxy Compounds
• Macrolides
• Thiazoles
• des-methyl, des-amino pateamine A
• pateamine A

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Epoxy Compounds (chemistry, pharmacology, therapeutic use)
• Female
• Humans
• Macrolides (chemistry, pharmacology, therapeutic use)
• Mice
• Mice, Nude
• Mice, SCID
• Neoplasms (drug therapy, pathology)
• Thiazoles (chemistry, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays