Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells

Evens, Andrew M.; Lecane, Philip; Magda, Darren; Prachand, Sheila; Singhal, Seema; Nelson, Jeff; Miller, Richard A.; Gartenhaus, Ronald B.; Li, Gordon

doi:10.1182/blood-2004-03-0964

Cited by 74 publications

(51 citation statements)

References 42 publications

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“…7). Catalase has been found to prevent MGd cell toxicity in vivo (Evens et al, 2005a). Addition of catalase plus SOD to the assays to prevent deleterious ROS from degrading heme and interfering with the reaction (Nagababu and Rifkind, 2004) gives rise to only a small recovery of activity with a corresponding increase in the IC 50 to 0.3 M. In contrast, MGd is a much less potent inhibitor (IC 50 ϭ 4.6 mM) in the reaction supported by ascorbate than in that supported by NADPH/CPR.…”

Section: P450 Reductase Inhibition and Anticancer Activity 195mentioning

confidence: 99%

Motexafin Gadolinium-Induced Cell Death Correlates with Heme oxygenase-1 Expression and Inhibition of P450 Reductase-Dependent Activities

Evans¹,

Xu²,

Sirisawad³

et al. 2007

Molecular Pharmacology

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Heme oxygenase-1 (HO1), which oxidizes heme to biliverdin, CO, and free iron, conveys protection against oxidative stress and is antiapoptotic. Under stress conditions, some porphyrin derivatives can inhibit HO1 and trigger cell death. Motexafin gadolinium (MGd) is an expanded porphyrin that selectively targets cancer cells through a process of futile redox cycling that decreases intracellular reducing metabolites and protein thiols. Here, we report that hematopoietic-derived cell lines that constitutively express HO1 are more susceptible to MGd-induced apoptosis than those that do not. MGd used in combination with tin protoporphyrin IX, an inhibitor of HO1, resulted in synergistic cell killing. Consistent with these cell culture observations, we found that MGd is an inhibitor of heme oxygenase-1 activity in vitro. We demonstrate that inhibition of HO1 reflects an interaction of MGd with NADPH-cytochrome P450 reductase, the electron donor for HO1, that results in diversion of reducing equivalents from heme oxidation to oxygen reduction. In accord with this mechanism, MGd is also an in vitro inhibitor of CYP2C9, CYP3A4, and CYP4A1. Inhibition of HO1 by MGd may contribute to its anticancer activity, whereas its in vitro inhibition of a broad spectrum of P450 enzymes indicates that a potential exists for drug-drug interactions.

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Section: P450 Reductase Inhibition and Anticancer Activity 195mentioning

confidence: 99%

Motexafin Gadolinium-Induced Cell Death Correlates with Heme oxygenase-1 Expression and Inhibition of P450 Reductase-Dependent Activities

Evans¹,

Xu²,

Sirisawad³

et al. 2007

Molecular Pharmacology

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“…MGd is an electron-affinic compound that mediates electron transfer from a variety of intracellular reducing species, such as ascorbate, NADPH, and thiols, to oxygen to form superoxide and hydrogen peroxide (17)(18)(19)(20). Recently, we generated gene expression profiles of plateau phase A549 lung cancer cell cultures treated with MGd and observed marked induction of transcript levels of genes that play major roles in controlling intracellular free zinc levels (6).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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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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“…Enhancement of ROS has been identified in cell culture models as a critical mechanism by which many anticancer agents, including avocado extracts, damage cancer cells [16][17][18][19]. Therefore, high endogenous levels of ROS have been thought to be a double-edged sword to cancer development [48,49].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, ROS may damage cellular DNA, which may lead to carcinogenesis [14,15]. Another well-documented phenomenon is that precancerous and cancerous cells contain an elevated level of endogenous ROS, and many cancer therapeutic agents eradiate these abnormal cells by further increasing the ROS [16][17][18][19]. Similarly, our previous studies showed that D003, a chloroform extract of avocado, induced apoptosis in human oral premalignant and malignant epithelial cells, but not normal primary cells, via an ROSmediated mechanism [11].…”

Section: Introductionmentioning

confidence: 99%

Avocado Extract Inhibits 7, 12-Dimethylbenz[a]anthracene (DMBA)- Induced Carcinogenesis in Hamster Cheek Pouches

Ding¹,

Casto²,

Deng³

et al. 2014

Med chem

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Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells

Cited by 74 publications

References 42 publications

Motexafin Gadolinium-Induced Cell Death Correlates with Heme oxygenase-1 Expression and Inhibition of P450 Reductase-Dependent Activities

Motexafin Gadolinium-Induced Cell Death Correlates with Heme oxygenase-1 Expression and Inhibition of P450 Reductase-Dependent Activities

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

Avocado Extract Inhibits 7, 12-Dimethylbenz[a]anthracene (DMBA)- Induced Carcinogenesis in Hamster Cheek Pouches

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