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Research Articles: Therapeutics, Targets, and Development

Eupalmerin acetate, a novel anticancer agent from Caribbean gorgonian octocorals, induces apoptosis in malignant glioma cells via the c-Jun NH₂-terminal kinase pathway

Departments of ¹ Neurosurgery and ² Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ³ Department of Chemistry, The University of Puerto Rico, San Juan, Puerto Rico

Requests for reprints: Yasuko Kondo, Department of Neurosurgery, Unit BSRB1004, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-834-6214; Fax: 713-834-6257. E-mail: yaskondo{at}mdanderson.org

Abstract

The marine ecosystem is a vast but largely untapped resource for potential naturally based medicines. We tested 15 compounds derived from organisms found in the Caribbean Sea (14 gorgonian octocoral–derived compounds and one sponge-derived compound) for their anticancer effects on human malignant glioma U87-MG and U373-MG cells. Eupalmerin acetate (EPA) was chosen as the lead compound based on its longer-term stability and greater cytotoxicity than those of the other compounds we tested in these cell types. EPA induced G₂-M cell cycle arrest and apoptosis via the mitochondrial pathway; it translocated Bax from the cytoplasm to the mitochondria and dissipated the mitochondrial transmembrane potential in both cell types. EPA was found to increase phosphorylated c-Jun NH₂-terminal kinase (JNK) by >50% in both U87-MG and U373-MG cells. A specific JNK inhibitor, SP600125, inhibited EPA-induced apoptosis, confirming the involvement of the JNK pathway in EPA-induced apoptotic cell death. Furthermore, 7 days of daily intratumoral injections of EPA significantly suppressed the growth of s.c. malignant glioma xenografts (P < 0.01, on day 19). These results indicate that EPA is therapeutically effective against malignant glioma cells in vitro and in vivo and that it, or a similar marine-based compound, may hold promise as a clinical anticancer agent. [Mol Cancer Ther 2007;6(1):184–92]

Grant support: USPHS U54 grant CA96033 (R.A. Newman, Y. Kondo, and A.D. Rodríguez) and Anthony D. Bullock III Foundation (S. Kondo and Y. Kondo). B. Vera is a scholar of the NIH-Minority Biomedical Research Support Program Support of Continuous Research Excellence Program/Research Initiative for Scientific Enhancement Program of the University of Puerto Rico.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: A. Iwamaru and E. Iwado contributed equally to this work.

Received 7/18/06; revised 10/31/06; accepted 11/27/06.