title: Anti-proliferative effect of (19Z)-halichondramide, a novel marine macrolide isolated from the sponge Chondrosia corticata, is associated with G2/M cell cycle arrest and suppression of mTOR signaling in human lung cancer cells.
abstract: Five oxazole-containing macrolides isolated from the marine sponge Chondrosia corticata were evaluated for their anti-proliferative activity in a panel of human solid cancer cell lines. (19Z)-Halichondramide ((19Z)-HCA), a novel trisoxazole-containing macrolide, exhibited the highest potency among the macrolides, with IC50 values in the submicro-molar ranges. Prompted by the high potency of growth inhibition of cancer cells, we investigated the mechanism of action of the anti-proliferative activity of (19Z)-HCA in human A549 lung cancer cells. (19Z)-HCA induced cell cycle arrest in the G2/M phase, and this event was highly correlated with the expression of checkpoint proteins, including the up-regulation of p53 and GADD45α and the down-regulation of cyclin B1, cyclin A, CDC2, and CDC25C. In addition, the growth inhibition by (19Z)-HCA was associated with the suppression of mTOR and its downstream effector molecules 4EBP1 and p70S6K. The modulation of mTOR signaling by (19Z)-HCA was found to be mediated by the regulation of upstream proteins, including the down-regulation of Akt and p38 MAPK and the up-regulation of AMPK. These data suggest the potential of (19Z)-HCA to serve as a candidate for cancer chemotherapeutic agents derived from marine organisms by virtue of arresting the cell cycle in the G2/M phase and the modulation of mTOR/AMPK signaling pathways.
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Bae
authors.forename: Gi Dae
authors.initials: GD
authors.lastname: Kim
authors.forename: Ju-Eun
authors.initials: JE
authors.lastname: Jeon
authors.forename: Jongheon
authors.initials: J
authors.lastname: Shin
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D011161:Porifera; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C495172:(19Z)-halichondramide; D000970:Antineoplastic Agents; D018942:Macrolides; D010080:Oxazoles; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases