This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Magda, D. Articles by Sessler, J. L. PubMed PubMed Citation Articles by Magda, D. Articles by Sessler, J. L.

Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores

¹ Pharmacyclics, Inc., Sunnyvale, California; ² Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California; and ³ Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas

Requests for reprints: Darren Magda, Pharmacyclics, Inc., 995 E. Arques Avenue, Sunnyvale, CA 94085. Phone: 408-774-3318; Fax: 408-774-0340; E-mail: dmagda{at}pcyc.com.

Key Words: pyrithione • zinc • thioredoxin reductase • motexafin gadolinium

Several water-solubilized versions of the zinc ionophore 1-hydroxypyridine-2-thione (ZnHPT), synthesized as part of the present study, have been found both to increase the intracellular concentrations of free zinc and to produce an antiproliferative activity in exponential phase A549 human lung cancer cultures. Gene expression profiles of A549 cultures treated with one of these water-soluble zinc ionophores, PCI-5002, reveal the activation of stress response pathways under the control of metal-responsive transcription factor 1 (MTF-1), hypoxia-inducible transcription factor 1 (HIF-1), and heat shock transcription factors. Additional oxidative stress response and apoptotic pathways were activated in cultures grown in zinc-supplemented media. We also show that these water-soluble zinc ionophores can be given to mice at 100 µmol/kg (300 µmol/m²) with no observable toxicity and inhibit the growth of A549 lung and PC3 prostate cancer cells grown in xenograft models. Gene expression profiles of tumor specimens harvested from mice 4 h after treatment confirmed the in vivo activation of MTF-1–responsive genes. Overall, we propose that water-solubilized zinc ionophores represent a potential new class of anticancer agents. [Cancer Res 2008;68(13):5318–25]