Specific IKKβ inhibitor IV blocks streptonigrin‐induced NF‐κB activity and potentiates its cytotoxic effect on cancer cells

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.

Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF-κB-Dependent Induction of SOCS1

“…To further demonstrate the role of NF-B in Tax-mediated induction of SOCS1, we used a cell permeable small molecule inhibitor with selectivity for IKK␤ (IKK2 inhibitor IV) (11). We first validated the inhibitor by demonstrating a potent block in TNF-induced activation of an NF-B luciferase reporter gene (Fig.…”

Natural Compounds' Activity against Cancer Stem-Like or Fast-Cycling Melanoma Cells

“…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].…”

Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques

“…Similar to the control IKK-β inhibitor (IKK-β inhibitor IV), 44 compound 8 inhibited TNF-α-induced luciferase activity dose-dependently. The inhibitory effect (IC 50 : 5.85 ± 0.97 μM, Fig.…”