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Issue 2, 2012
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Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells

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Abstract

Clinical debate has arisen over the consequences of antioxidant supplementation during cancer chemotherapy. While antioxidants may impede the efficacy of chemotherapy by scavenging reactive oxygen species and free radicals, it is also possible that antioxidants alleviate unwanted chemotherapy-induced toxicity, thus allowing for increased chemotherapy doses. These contradictory assertions suggest that antioxidant supplementation during chemotherapy treatment can have varied outcomes depending on the cellular context. To gain a more robust understanding of the role that antioxidants play in chemotherapy, we investigated the dose-dependent effects of the antioxidant, N-acetylcysteine (NAC), on the redox-mediated regulation of intracellular signaling. In this study, we systematically evaluated the effect of Dox-induced ROS on the NF-κB pathway in a pediatric acute lymphoblastic leukemia (ALL) cell line by measuring the thiol-based oxidative modifications of redox-sensitive proteins within the pathway. We report a functional consequence of NAC supplementation during doxorubicin (Dox) chemotherapy administration via the NF-kappa B (NF-κB) signal transduction pathway. The ability of NAC to alter Dox-induced NF-κB activity is contingent on the ROS-mediated S-glutathionylation of IKK-β. Moreover, the NAC-dependent alteration of intracellularglutathione redox balance, through pro-oxidant and antioxidant mechanisms, can be exploited to either promote or inhibit Dox-induced NF-κB activity in an NAC-concentration-dependent manner. We developed an electron-transfer-based computational model that predicts the effect of NAC pretreatment on Dox-induced NF-κB signaling for a range of NAC and Dox treatment combinations.

Graphical abstract: Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells

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Publication details

The article was received on 29 Jul 2011, accepted on 11 Nov 2011 and first published on 01 Dec 2011


Article type: Paper
DOI: 10.1039/C1MB05315A
Citation: Mol. BioSyst., 2012,8, 650-662
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    Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells

    N. A. Finn and M. L. Kemp, Mol. BioSyst., 2012, 8, 650
    DOI: 10.1039/C1MB05315A

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