Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A.
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.
Division of Biological Research, and 3Scientific Administration, Eisai Research Institute of Boston, Inc, Andover, Massachusetts 01810, USA.
Galina
G
Kuznetsov
Qunli
Q
Xu
Lori
L
Rudolph-Owen
Karen
K
Tendyke
Junke
J
Liu
Murray
M
Towle
Nanding
N
Zhao
Joanne
J
Marsh
Sergei
S
Agoulnik
Natalie
N
Twine
Lana
L
Parent
Zhihong
Z
Chen
Jue-Lon
JL
Shie
Yimin
Y
Jiang
Huiming
H
Zhang
Hong
H
Du
Roch
R
Boivin
Yuan
Y
Wang
Daniel
D
Romo
Bruce A
BA
Littlefield
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D018942:Macrolides; D013844:Thiazoles; C567944:des-methyl, des-amino pateamine A; C421324:pateamine A