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Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines

¹ Pharmacyclics, Inc., Sunnyvale, California and ² Institute for Genetic Medicine, University of Southern California, Los Angeles, California

Requests for reprints: Darren Magda, Pharmacyclics, Inc., 995 E. Arques Avenue, Sunnyvale, CA 94085. Phone: 408-774-3318; Fax: 408-328-3689; E-mail: dmagda{at}pcyc.com.

There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element–binding transcription factor-1 (MTF-1)–regulated and hypoxia-inducible transcription factor-1 (HIF-1)–regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1– and HIF-1–regulated transcripts as well as additional transcripts regulated by NF-E2–related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies. (Cancer Res 2005; 65(24): 11676-88)

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