Iron depletion: Possible cause of tumor cell cytotoxicity induced by activated macrophages

Hibbs, John B.; Taintor, Read R.; Vavrin, Zdenek

doi:10.1016/0006-291x(84)90288-2

Cited by 178 publications

(87 citation statements)

References 9 publications

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“…iron metabolism ͉ iron transport ͉ dinitrosyl iron complexes N itrogen monoxide (NO) is an effector molecule with many roles, e.g., smooth muscle relaxation, blood clotting, and the cytotoxicity of activated macrophages (M s) against tumors (1)(2)(3)(4)(5). The nitric oxide synthase (NOS) family of enzymes generate NO, and many of its functions are mediated by its binding to Fe in heme and nonheme Fe-containing proteins (4)(5)(6)(7)(8)(9)(10).…”

Section: Nitrogen Monoxide (No)-mediated Iron Release From Cells Is Lmentioning

confidence: 99%

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Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Watts

Hawkins

Ponka

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

116

119

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Nitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron (Fe) release. We have shown that NO-mediated Fe efflux from cells required glutathione (GSH), and we have hypothesized that a GS–Fe–NO complex was released. Hence, we studied the role of the GSH-conjugate transporter multidrug resistance-associated protein 1 (MRP1) in NO-mediated Fe efflux. MCF7-VP cells overexpressing MRP1 exhibited a 3- to 4-fold increase in NO-mediated 59 Fe and GSH efflux compared with WT cells (MCF7-WT) over 4 h. Similar results were found for other MRP1-overexpressing cell types but not those expressing another drug efflux pump, P-glycoprotein. NO-mediated 59 Fe and GSH efflux were temperature- and energy-dependent and were significantly decreased by the GSH-depleting agent and MRP1 transport inhibitor l -buthionine-[ S , R ]-sulfoximine. Other MRP1 inhibitors, MK571, probenecid, and difloxacin, significantly inhibited NO-mediated 59 Fe release. EPR spectroscopy demonstrated the dinitrosyl-dithiol-Fe complex (DNIC) peak in NO-treated cells was increased by MRP1 inhibitors, indicating inhibited DNIC transport from cells. The extent of DNIC accumulation correlated with the ability of MRP1 inhibitors to prevent NO-mediated 59 Fe efflux. MCF7-VP cells were more sensitive than MCF7-WT cells to growth inhibition by effects of NO, which was potentiated by l -buthionine-[ S , R ]-sulfoximine. These data indicate the importance of GSH in NO-mediated inhibition of proliferation. Collectively, NO stimulates Fe and GSH efflux from cells via MRP1. Active transport of NO by MRP1 overcomes diffusion that is inefficient and nontargeted, which has broad ramifications for understanding NO biology.

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Section: Nitrogen Monoxide (No)-mediated Iron Release From Cells Is Lmentioning

confidence: 99%

“…Tumor cells cocultured with M s exhibit decreased DNA synthesis and a pronounced loss of Fe (1,2). The Fe released may be from [Fe-S]-containing proteins (2,8,11) and could be a complex of NO and thiol-containing ligands e.g., reduced glutathione (GSH) (12)(13)(14).…”

Section: Nitrogen Monoxide (No)-mediated Iron Release From Cells Is Lmentioning

confidence: 99%

Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Watts

Hawkins

Ponka

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

116

119

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“…Hibbs and colleagues demonstrated several important facts; A) that macrophagemediated killing of tumor cells was dependent on Larginine 3 , B) that L-arginine was metabolized to L-citrulline in the process, and that one of the guanidino nitrogens of arginine was oxidized to produce nitrite 4 . They also demonstrated C) that macrophages mediated the loss of aconitase activity 5 , caused the depletion of Fe 6 , and mediated the inhibition of mitochondrial respiration in tumor cells 7 . The occurrence of this research effort is remarkably near the same time (from early 1980 up to late 1987) that extensive research activity was also occurring independently by many groups especially those led by Ignarro, Moncada and Furchgott that led to the discovery that EDRF was equivalent to NO [8][9][10] .…”

Section: Historical Observationsmentioning

confidence: 94%

Nitric Oxide and Cancer Development

et al. 2007

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Abstract:The role of nitric oxide (NO) in cancer development has become a very active research area. This review presents an overview of many studies that implicate an important role of NO in the development of cancer. These include results in experimental models as well as many observations made on NO and inducible nitric oxide synthase (iNOS) in human cancers. Our survey of the literature has allowed us to conclude that in general large levels of NO will kill cancer cells but paradoxically at intermediate to lower levels NO prevents cancer cell apoptosis and enhances tumor growth. This basic tenet has been demonstrated in many experimental models. The mechanistic basis of how intermediate levels of NO mediate tumor development is an active area of research and is the subject of this review. NO mediated S-nitrosylation of key enzymes and regulatory proteins plays a critical role. Key proteins S-nitrosylated which enhance tumor development include several caspases involved in apoptosis, PTEN the tumor suppressor protein, Bcl-2 the mitochondrial protein which protects from apoptosis, OGG1 the DNA repair protein and methionine adenosyl transferase the liver protein which synthesizes adenosylmethionine. The S-nitrosylation of these proteins enhances DNA mutations, prevents cancer cell apoptosis and enhances oncogenic cell growth. (J Toxicol Pathol 2007; 20: 77-92)

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“…Synthesis of this enzyme is triggered by binding of β-glucan to a PRR on the macrophage surface. Formed nitric oxide induces a cytotoxic effect upon tumor cells (Hibbs et al, 1984;Stuehr and Nathan, 1989) and shows distinct impact on many pathogens (Grangeer et al, 1988;James and Claven, 1989).On the other hand, it can also damage tissues and DNA (Billar, 1995) and high concentrations can cause septic shock. The sustained action of the activator induces expression of iNOS, and increased formation of NO results in vasodilatation of veins.…”

Section: Side Effectsmentioning

confidence: 99%

β-Glucans, History, and the Present: Immunomodulatory Aspects and Mechanisms of Action

Novák

Větvička²

2008

Journal of Immunotoxicology

288

219

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The present paper represents a comprehensive up-to-date review of β-glucans, their chemical and biological properties, and their role in immunological reactions. β-D-Glucans belong to a group of physiologically active compounds called biological response modifiers and represent highly conserved structural components of cell walls in yeast, fungi, or seaweed. Despite almost 150 years of research, the exact mechanisms of their action remain unclear. The present review starts with the history of glucans. Next, attention is focused on sources and structure, comparing the effects of physicochemical properties, and sources on biological effects. As glucans belong to natural products useful in preventing various diseases, they have been highly sought after throughout human history. Based on extensive recent research, this paper explains the various mechanisms of effects and the ways glucans mediate their effects on defense reactions against infections. Despite the fact that predominately pharmacological effects of glucans are positive, their unfavorable and potentially toxic side effects were not overlooked. In addition, attention was focused on the future research, possible alternatives such as synthetic oligosaccharides, and on clinical applications.

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Iron depletion: Possible cause of tumor cell cytotoxicity induced by activated macrophages

Cited by 178 publications

References 9 publications

Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

Nitric Oxide and Cancer Development

β-Glucans, History, and the Present: Immunomodulatory Aspects and Mechanisms of Action

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