Specific IKKbeta inhibitor IV blocks Streptonigrin-induced NF-kappaB activity and potentiates its cytotoxic effect on cancer cells.
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.
Gavriil
Maria
M
Department of Oncology, Wyeth Research, Pearl River, New York, USA.
Tsao
Cheng-Chung
CC
Mandiyan
Sreekala
S
Arndt
Kim
K
Abraham
Robert
R
Zhang
Yixian
Y
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013308:Streptonigrin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013308:Streptonigrin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D020169:Caspases