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      N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells

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          Abstract

          Background

          Liver cancer is one of the most common malignancies in the world and at the moment, there is no drug intervention effective for the treatment of liver tumours. Investigate the effect of N-acetylcysteine (NAC), which has been studied for its antitumoural properties, on the toxicity of hepatocarcinoma (HCC) cells in vitro when used with the drug interferon alpha-2A (IFN), which is used clinically to treat HCC.

          Results

          NAC, IFN and NAC plus IFN reduced cell viability, as determined by MTT assay. More importantly, NAC potentiates the cytotoxic effect of IFN, with the best response achieved with 10 mM of NAC and 2.5 x 10 4 of IFN. These results were confirmed by Annexin/PI staining through flow cytometry and morphologic analyses. Co-treatment reduced the expression of the nuclear transcription factor kappa-B (NF-kB). In a similar way to NAC, RNAi against p65 potentiated the toxic effect of IFN, suggesting that, indeed, NAC may be enhancing the effect of IFN through inhibition of NF-kB.

          Conclusions

          Our results support the notion that NAC may be an important drug for the treatment of liver tumours as primary or adjuvant therapy. IFN has a limited clinical response, and therefore, the anti-proliferative properties of NAC in the liver should be explored further as an alternative for non-responders to IFN treatment.

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          Most cited references 51

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          Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.

          Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
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            Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression.

            Abundant data support a key role for the transcription factor nuclear factor-kappaB (NF-kappaB) signaling pathway in controlling the initiation and progression of human cancer. NF-kappaB and associated regulatory proteins such as IkappaB kinase (IKK) are activated downstream of many oncoproteins and there is much evidence for the activation of NF-kappaB-dependent target genes in a variety of solid tumors and hematologic malignancies. This review focuses on the mechanisms by which the NF-kappaB pathway is activated in cancer and on the oncogenic functions controlled by activated NF-kappaB. Additionally, the effects of NF-kappaB activation in tumors relative to cancer therapy are also discussed.
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              Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs.

              The cytotoxicity of chemotherapeutic agents is attributed to apoptosis. Acquired resistance to the effects of chemotherapy has emerged as a significant impediment to effective cancer therapy. One feature that cytotoxic treatments of cancer have in common is their activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which regulates cell survival. NF-kappaB activation suppresses the apoptotic potential of chemotherapeutic agents and contributes to resistance. What evidence is there that inhibitors of NF-kappaB might promote apoptosis in cancer cells and can NF-kappaB inhibitors be used to overcome resistance to chemotherapeutic agents?
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                Author and article information

                Journal
                Comp Hepatol
                Comp Hepatol
                Comparative Hepatology
                BioMed Central
                1476-5926
                2012
                4 December 2012
                : 11
                : 4
                Affiliations
                [1 ]Post-Graduation Program in Medicine: Hepatology. Universidade Federal de Ciências da Saúde de Porto Alegre. Brazil. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, CEP: 90050-170, Brazil
                [2 ]Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, CEP: 90035-903, Brazil
                [3 ]Pos-Graduated Program in Cell Biology, Universidade Federal do Rio Grande do Sul, Brazil, Porto Alegre, RS, CEP 91501-970, Brazil
                Article
                1476-5926-11-4
                10.1186/1476-5926-11-4
                3539937
                23206959
                Copyright ©2012 Kretzmann et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research

                Gastroenterology & Hepatology

                n-acetylcysteine, interferon alpha, nf-kb, liver cancer cells

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