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: Song Yi Bae, Gi Dae Kim, Ju-Eun Jeon, Jongheon Shin, Sang Kook Lee
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 27 Issue 2 Pg. 694-9 (Mar 2013) ISSN: 1879-3177 [Electronic] England
• PMID: 23147639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• (19Z)-halichondramide
• Antineoplastic Agents
• Macrolides
• Oxazoles
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• G2 Phase (drug effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Macrolides (pharmacology)
• Mitogen-Activated Protein Kinases (metabolism)
• Oxazoles (pharmacology)
• Porifera
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)