Specific IKKbeta inhibitor IV blocks Streptonigrin-induced NF-kappaB activity and potentiates its cytotoxic effect on cancer cells.

Department of Oncology, Wyeth Research, Pearl River, New York, USA.
Molecular Carcinogenesis (Impact Factor: 4.81). 08/2009; 48(8):678-84. DOI: 10.1002/mc.20550
Source: PubMed

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.

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    • "Streptonigrin is converted by NAD(P)H:quinine oxidoreductase (NQO1) to the more active hydroquinone form. Therefore, tumors containing high levels of this enzyme might be sensitive to streptonigrin at concentrations that do not generate severe side effects [39]. It was also shown that streptonigrin at 0.05 µM markedly decreased clonogenic survival of pancreatic cancer cells expressing NQO1 at elevated levels but not of colorectal cancer cells with lower levels of this enzyme [40]. "
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