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Research Articles: Therapeutics, Targets, and Development

Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma

¹ The Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas and ² Department of Medicine, Arizona Cancer Center, University of Arizona, Tucson, Arizona

Requests for reprints: John D. Shaughnessy, Jr., The Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR. E-mail: shaughnessyjohn{at}umas.edu

Abstract

High-risk multiple myeloma can be correlated with amplification and overexpression of the cell cycle regulator CKS1B. Herein, we used the COMPARE algorithm to correlate high expression of CKS1B mRNA in the NCI-60 cell line panel with the concentration causing 50% growth inhibition (GI₅₀) of >40,000 synthetic compounds. This led to the identification of NSC 338258 (EPED3), a highly stable, hydrophilic derivative of the plant alkaloid ellipticine. In vitro, this synthetic anticancer compound exhibits dramatic cytotoxic activity against myeloma cells grown in suspension or in coculture with stromal cells. EPED3-induced cell cycle arrest and an apoptotic progression that appear to be a consequence of the instantaneous effect of the drug on cytoplasmic organelles, particularly mitochondria. Disruption of mitochondria and cytoplasmic distribution of cytochrome c initiated the intracellular proteolytic cascade through the intrinsic apoptotic pathway. EPED3 is able to induce apoptosis in myeloma cells with de novo or acquired resistance to commonly administered antimyeloma agents. Collectively, our data suggest that EPED3 targets mitochondrial function to rapidly deplete chemical energy and initiate apoptosis in myeloma cells at nanomolar concentrations while leaving stromal cells unharmed. [Mol Cancer Ther 2008;7(3):500–9]

Grant support: NIH grants CA55819 (J.D. Shaughnessy, Jr. and B. Barlogie) and CA97513 (J.D. Shaughnessy, Jr.), Fund to Cure Myeloma, and Nancy and Stephen Grand Philanthropic Fund.

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.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁴ E. Tian, unpublished data.

Received 8/ 2/07; revised 12/ 4/07; accepted 2/ 1/08.