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Research Articles: Therapeutics, Targets, and Development

Levels of p27^kip1 determine Aplidin sensitivity

¹ Experimental Therapeutics Programme and ² Structural Biology and Biocomputing Programme, Spanish National Cancer Center; ³ PharmaMar R&D, Madrid, Spain

Requests for reprints: Amancio Carnero, Experimental Therapeutics Programme, Centro Nacional de Investigaciones Oncológicas, c/Melchor Fernandez Almagro n°3, 28029 Madrid, Spain. Phone: 34-91-732-8021; Fax: 34-91-224-6976. E-mail: acarnero{at}cnio.es

Abstract

Aplidin (plitidepsin) is a novel anticancer drug isolated from the marine tunicate Aplidium albicans. Aplidin shows potent antitumor activity in preclinical models against a wide variety of human tumors. Aplidin is currently in phase II clinical trials in a variety of solid tumors and hematologic malignancies. Moreover, clinical studies of Aplidin in combination with other agents are ongoing because it generally lacks cross-resistance with other known cytotoxic drugs. The mode of action of Aplidin in tumor cells is only partially understood. Aplidin induces an early oxidative stress response, which results in a rapid and sustained activation of the epidermal growth factor receptor, the nonreceptor protein tyrosine kinase Src, and the serine threonine kinases c-Jun NH₂-terminal kinase and p38 mitogen-activated protein kinase. Here, we show that sensitivity to Aplidin correlates inversely with the levels of expression of the cyclin-dependent kinase inhibitor p27^kip1 (p27) in a panel of low passaged human sarcoma cell lines. Aplidin induces p27 through an oxidation-dependent mechanism and the reduction of p27 levels by specific short hairpin RNA increases Aplidin sensitivity. We confirmed these results in p27 null mouse embryonic fibroblasts corroborating the specificity of the p27 role in Aplidin response because p21^waf1 null mouse embryonic fibroblasts do not show this increased sensitivity. We propose a mechanism of action of Aplidin involving p27 and support the analysis of p27 in the response to Aplidin in currently ongoing clinical trials to establish the levels of this protein as response predictor. [Mol Cancer Ther 2007;6(4):1310–6]

Grant support: Fondo de Investigación Sanitaria, Fundacion Mutua Madrileña, and Ministerio de Ciencia y Tecnología (A. Carnero).

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.

Received 11/27/06; revised 2/12/07; accepted 2/26/07.