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

ABSTRACT: We report the effect of motexafin gadolinium (MGd) and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, cell cycle, 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 apoptotic response. Treatment with exogenous zinc increased oxidative stress and, conversely, oxidative stress resulted in increased intracellular free zinc levels. To better understand the molecular basis of these results, 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 MTF-1 and HIF-1 regulated genes. Cultures co-treated 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 NRF-2. Overall, these studies suggest that co-treatment of Ramos cells with MGd and zinc acetate increase intracellular zinc levels with a concomitant rise in oxidative stress levels that activate adaptive survival responses but eventually lead to cell death. Keywords: Dose response

ORGANISM(S): Homo sapiens

PROVIDER: GSE2964 | GEO | 2006/01/01

SECONDARY ACCESSION(S): PRJNA92641

REPOSITORIES: GEO

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Project description:Previous evaluation by different molecular and physiological assays of Staphylococcus aureus (S. aureus) responses to heat shock exposure yielded a still fragmentary view of the mechanisms determining bacterial survival or death at supra-physiological temperatures. This study analyzed diverse facets of S. aureus heat-shock adjustment by recording global transcriptomic and metabolic responses of bacterial cultures shifted for 10 min from 37oC to a sub-lethal (43oC) or eventually lethal (48oC) temperature. A relevant metabolic model of the combined action of specific stress response mechanisms with more general, energy-regulating metabolic pathways in heat-shocked S. aureus was designed. While S. aureus cultures shifted to 43oC or left at 37oC showed marginal differences in growth and survival rates, bacterial cultures exposed to 48oC showed a rapid growth arrest followed by a subsequent decline in viable counts. The most substantial heat shock-induced changes at both 43oC and 48oC occurred in transcript levels of HrcA- and CtsR-regulated genes, encoding classical chaperones DnaK and GroESL, and some Hsp100/Clp ATPases components, respectively. Other metabolic pathways up-regulated by S. aureus exposure at 48oC included genes encoding several enzymes coping with oxidative stress, and DNA damage, or/and impaired osmotic balance. Some major components of the pentose phosphate cycle and gluconeogenesis were also up-regulated, which reflected depletion of free glucose by bacterial cultures grown in Mueller-Hinton broth prior to heat shock. In contrast, most purine- and pyrimidine-synthesis pathway components and amino acyl-tRNA synthetases were down-regulated at 48oC, as well as arginine deiminase and major fermentative pathway components, such as alcohol, lactate and formate dehydrogenases. Despite the heat-induced, increased requirements for ATP-dependent macromolecular repair mechanisms combined with declining energy sources, intracellular ATP levels remained remarkably constant during heat shock. In conclusion, the sequential loss of replication and viability at 48oC cannot be explained by significant reductions in intracellular ATP levels, but may reflect ATP rerouting for macromolecular repair mechanisms and cell survival. Our metabolic model also suggests that heat-stressed S. aureus should down-regulate the production of potential, DNA-damaging reactive oxygen species that might result from electron transport-generated ATP, involving excessive levels of free heavy metals, in particular iron. Keywords: Staphylococcus aureus; heat shock; stress responses; transcriptomic profiling; physiological adjustment Comparative transcriptomic profiling of late log phase cultures of S. aureus ISP794, exposed to 43Â°C vs. 37Â°C, or 48Â°C vs. 37Â°C. We performed triplicate measurements from independently grown cultures for each heat stress condition.

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

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