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Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

¹ Pharmacyclics, Inc., Sunnyvale, California; ² Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania; and ³ Institute for Genetic Medicine, University of Southern California, Los Angeles, California

Requests for reprints: Joseph G. Hacia, Institute for Genetic Medicine, University of Southern California, 2250 Alcazar Street, IGM 240, Los Angeles, CA 90089. Phone: 323-442-3030; Fax: 323-442-2764; E-mail: hacia{at}hsc.usc.edu.

To gain a better understanding of the mechanism of action of the metal cation–containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer.

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