Abstract
Many anticancer agents activate NF-kappaB, which plays an important role in the survival of cancer cells. Inhibition of NF-kappaB activity may therefore potentiate the efficacy of anticancer agents. We found that a previously used anticancer agent Streptonigrin (SN) was also a potent NF-kappaB inducer. Using a specific IKKbeta inhibitor IV (Podolin et al., J Pharmacol Exp Ther 2005; 312: 373-381), we revealed that the activation of NF-kappaB was mediated through DNA damage-induced activation of IKK complex. Furthermore, we demonstrated that SN-induced DNA damage was unrelated to reactive oxygen species but to the hydroquinone form of SN converted by the NAD(P)H:quinine oxidoreductase (NQO1). The study suggests that the combination of SN with IKK inhibitor may improve efficacy over the use of single agent.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology*
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Blotting, Western
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Caspases / metabolism
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Cell Proliferation / drug effects
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DNA Damage
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Enzyme Inhibitors / pharmacology*
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Histones / genetics
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Histones / metabolism
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Humans
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I-kappa B Kinase / antagonists & inhibitors*
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Melanoma / drug therapy*
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Melanoma / metabolism
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Melanoma / pathology
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NAD(P)H Dehydrogenase (Quinone) / genetics
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NAD(P)H Dehydrogenase (Quinone) / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Phosphorylation / drug effects
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Reactive Oxygen Species / metabolism
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Streptonigrin / pharmacology*
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Tumor Cells, Cultured
Substances
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Antibiotics, Antineoplastic
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Enzyme Inhibitors
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H2AX protein, human
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Histones
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NF-kappa B
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Reactive Oxygen Species
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Streptonigrin
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NAD(P)H Dehydrogenase (Quinone)
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NQO1 protein, human
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I-kappa B Kinase
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IKBKB protein, human
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Caspases