Alteration of subcellular redox equilibrium and the consequent oxidative modification of nuclear factor kappaB are critical for anticancer cytotoxicity by emodin, a reactive oxygen species-producing agent.
We previously found that emodin produced reactive oxygen species (ROS) intracellularly. In various tumor cells at low doses it enhances the cytotoxicity of As(2)O(3), and at higher doses it renders cytotoxicity independently in vitro and in vivo. The effects involve redox-mediated inhibition of NF-kappaB activation. In this study, we focus on the mechanisms by which emodin inhibits NF-kappaB activation. Results in HeLa cells demonstrated that emodin at high doses or in combination with As(2)O(3), via generation of ROS especially in the nucleus, altered subcellular redox equilibrium and thus oxidized the redox-sensitive site on NF-kappaB and prevented its binding to the target DNA. In vivo study showed that tumors exposed to the arsenic/emodin cotreatment had dramatically smaller sizes and weaker antioxidant capacity, compared with arsenic alone. NF-kappaB binding and transactivation were inhibited in these tumors. These data help in the understanding of the mechanisms by which manipulation of cellular redox and NF-kappaB activation may enhance chemotherapy.
Jing
Yawu
Y
Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Yang
Jie
J
Wang
Yumei
Y
Li
Hui
H
Chen
Yuying
Y
Hu
Qingshen
Q
Shi
Guiying
G
Tang
Xueming
X
Yi
Jing
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004642:Emodin / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010087:Oxides / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D001152:Arsenicals; D004273:DNA, Neoplasm; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D016877:Oxidants; D010087:Oxides; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004642:Emodin; D000077237:Arsenic Trioxide