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

Abstract

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)

Prognostic significance of metallothionein in B-cell lymphomas

“…Potentially interesting options in this respect are electron-affinic compounds such as motexafin gadolinium, which increases oxidative stress, enhances expression of metal response element-binding transcription factor-1-regulated genes, including MT, and can induce cell-cycle arrest and apoptosis in B-cell lines in vitro under appropriate conditions. 37 Since cells may be more susceptible if already subjected to oxidative stress, both the MT high DLBCL described in this report and the recently identified so-called OxPhos consensus cluster of DLBCL, characterized by increased levels of several genes associated with oxidative phosphorylation, 17 could constitute interesting targets for future investigations in clinical trials.…”

Novel biomolecule lycopene-reduced graphene oxide-silver nanoparticle enhances apoptotic potential of trichostatin A in human ovarian cancer cells (SKOV3)

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The Antitumor Agent Imexon Activates Antioxidant Gene Expression: Evidence for an Oxidative Stress Response

“…Several anticancer drugs have been shown to increase reactive oxygen species, including doxorubicin, mitomycin C, arsenic trioxide, and motexafin-gadolinium, which may contribute to their antitumor activity (43,44). Apparently, an increase in reactive oxygen species contributes to the antitumor activity of imexon, although this may not be the major mechanism.…”