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Comparative Hepatology
Published in: Comparative Hepatology 1/2012

Open Access 01-12-2012 | Research

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

Authors: Nelson Alexandre Kretzmann, Eduardo Chiela, Ursula Matte, Norma Marroni, Claudio Augusto Marroni

Published in: Comparative Hepatology | Issue 1/2012

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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 104 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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Literature
1.
Pache I, Bize P, Halkic N, Montemurro M, Giostra E, Majno P, Moradpour D: [Management of hepatocellular carcinoma]. Rev Med Suisse. 2010, 6: 198-202.PubMed
2.
3.
4.
Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet J: Molecular Classification and Novel Targets in Hepatocellular Carcinoma: Recent Advancements. Semin Liver Dis. 2010, 30: 35-51. 10.1055/s-0030-1247131.PubMedCentralCrossRefPubMed
5.
El-Bassiouni A, Nosseir M, Zoheiry M, El-Ahwany E, Ghali A, El-Bassiouni N: Immunohistochemical expression of CD95 (Fas), c-myc and epidermal growth factor receptor in hepatitis C virus infection, cirrhotic liver disease and hepatocellular carcinoma. APMIS. 2006, 114: 420-427. 10.1111/j.1600-0463.2006.apm_323.x.CrossRefPubMed
6.
Nguyen H, Sankaran S, Dandekar S: Hepatitis C virus core protein induces expression of genes regulating immune evasion and anti-apoptosis in hepatocytes. Virology. 2006, 354: 58-68. 10.1016/j.virol.2006.04.028.CrossRefPubMed
7.
Goldstein D, Laszlo J: The role of interferon in cancer therapy: a current perspective. CA Cancer J Clin. 1988, 38: 258-277. 10.3322/canjclin.38.5.258.CrossRefPubMed
8.
Zhuang P, Zhang J, Zhang W, Zhu X, Liang Y, Xu H, Xiong Y, Kong L, Wang L, Wu W, Tang Z, Qin L, Sun H: Long-term interferon-alpha treatment suppresses tumor growth but promotes metastasis capacity in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2010, 136: 1891-1900. 10.1007/s00432-010-0848-1.CrossRefPubMed
9.
Guo L, Guo Y, Xiao S: Expression of tyrosine kinase Etk/Bmx and its relationship with AP-1- and NF-kappaB-associated proteins in hepatocellular carcinoma. Oncology. 2007, 72: 410-416. 10.1159/000113491.CrossRefPubMed
10.
Zingarelli B, Sheehan M, Wong HR: Nuclear factor-kappaB as a therapeutic target in critical care medicine. Crit Care Med. 2003, 31: S105-S111. 10.1097/00003246-200301001-00015.CrossRefPubMed
11.
Dutta J, Fan Y, Gupta N, Fan G, Gélinas C: Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene. 2006, 25: 6800-6816. 10.1038/sj.onc.1209938.CrossRefPubMed
12.
Tas S, Vervoordeldonk M, Tak P: Gene therapy targeting nuclear factor-kappaB: towards clinical application in inflammatory diseases and cancer. Curr Gene Ther. 2009, 9: 160-170. 10.2174/156652309788488569.PubMedCentralCrossRefPubMed
13.
Duan W, Jin X, Li Q, Tashiro S, Onodera S, Ikejima T: Silibinin induced autophagic and apoptotic cell death in HT1080 cells through a reactive oxygen species pathway. J Pharmacol Sci. 2010, 113: 48-56. 10.1254/jphs.09315FP.CrossRefPubMed
14.
Luo J, Kamata H, Karin M: The anti-death machinery in IKK/NF-kappaB signaling. J Clin Immunol. 2005, 25: 541-550. 10.1007/s10875-005-8217-6.CrossRefPubMed
15.
Nakanishi C, Toi M: Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer. 2005, 5: 297-309. 10.1038/nrc1588.CrossRefPubMed
16.
Lin Y, Bai L, Chen W, Xu S: The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets. 2010, 14: 45-55. 10.1517/14728220903431069.PubMedCentralCrossRefPubMed
17.
Fillmann H, Kretzmann N, San-Miguel B, Llesuy S, Marroni N, González-Gallego J, Tuñón M: Glutamine inhibits over-expression of pro-inflammatory genes and down-regulates the nuclear factor kappaB pathway in an experimental model of colitis in the rat. Toxicology. 2007, 236: 217-226. 10.1016/j.tox.2007.04.012.CrossRefPubMed
18.
Millea P: N-acetylcysteine: multiple clinical applications. Am Fam Physician. 2009, 80: 265-269.PubMed
19.
Moreno-Otero R, Trapero-Marugán M: Hepatoprotective effects of antioxidants in chronic hepatitis C. World J Gastroenterol. 2010, 16: 1937-1938. 10.3748/wjg.v16.i15.1937.PubMedCentralCrossRefPubMed
20.
Wanamarta A, van Rijn J, Blank L, Haveman J, van Zandwijk N, Joenje H: Effect of N-acetylcysteine on the antiproliferative action of X-rays or bleomycin in cultured human lung tumor cells. J Cancer Res Clin Oncol. 1989, 115: 340-344. 10.1007/BF00400960.CrossRefPubMed
21.
Morley N, Curnow A, Salter L, Campbell S, Gould D: N-acetyl-L-cysteine prevents DNA damage induced by UVA, UVB and visible radiation in human fibroblasts. J Photochem Photobiol B. 2003, 72: 55-60. 10.1016/j.jphotobiol.2003.06.004.CrossRefPubMed
22.
De Flora S, D’Agostini F, Masiello L, Giunciuglio D, Albini A: Synergism between N-acetylcysteine and doxorubicin in the prevention of tumorigenicity and metastasis in murine models. Int J Cancer. 1996, 67: 842-848. 10.1002/(SICI)1097-0215(19960917)67:6<842::AID-IJC14>3.0.CO;2-3.CrossRefPubMed
23.
Denizot F, Lang R: Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods. 1986, 89: 271-277.PubMed
24.
Gutierrez MB, Miguel BS, Villares C, Gallego JG, Tunon MJ: Oxidative stress induced by Cremophor EL is not accompanied by changes in NF-kappaB activation or iNOS expression. Toxicology. 2006, 222: 125-131. 10.1016/j.tox.2006.02.002.CrossRefPubMed
25.
Brasil LJ, San-Miguel B, Kretzmann NA, Amaral JL, Zettler CG, Marroni N, Gonzalez-Gallego J, Tunon MJ: Halothane induces oxidative stress and NF-kappaB activation in rat liver: protective effect of propofol. Toxicology. 2006, 227: 53-61. 10.1016/j.tox.2006.07.013.CrossRefPubMed
26.
Tichopad A, Bar T, Pecen L, Kitchen R, Kubista M, Pfaffl M: Quality control for quantitative PCR based on amplification compatibility test. Methods. 2010, 50: 308-312. 10.1016/j.ymeth.2010.01.028.CrossRefPubMed
27.
28.
Yano H: Inhibitory function of interferon on hepatocarcinogenesis. Oncology. 2008, 75 (Suppl 1): 22-29.CrossRefPubMed
29.
Yano H, Basaki Y, Oie S, Ogasawara S, Momosaki S, Akiba J, Nishida N, Kojiro S, Ishizaki H, Moriya F, et al: Effects of IFN-alpha on alpha-fetoprotein expressions in hepatocellular carcinoma cells. J Interferon Cytokine Res. 2007, 27: 231-238. 10.1089/jir.2006.0135.CrossRefPubMed
30.
Caglar M, Sari O, Akcan Y: Prediction of therapy response to interferon-alpha in chronic viral hepatitis-B by liver and hepatobiliary scintigraphy. Ann Nucl Med. 2002, 16: 511-514. 10.1007/BF02988654.CrossRefPubMed
31.
Guan D, Xu Y, Yang M, Wang H, Wang X, Shen Z: N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway. Mol Carcinog. 2010, 49: 68-74.PubMed
32.
Herzer K, Hofmann T, Teufel A, Schimanski C, Moehler M, Kanzler S, Schulze-Bergkamen H, Galle P: IFN-alpha-induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res. 2009, 69: 855-862. 10.1158/0008-5472.CAN-08-2831.CrossRefPubMed
33.
Lim dY, Jeong Y, Tyner A, Park J: Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol. 2007, 292: G66-G75.CrossRef
34.
Bekisz J, Baron S, Balinsky C, Morrow A, Zoon K: Antiproliferative Properties of Type I and Type II Interferon. Pharmaceuticals (Basel). 2010, 3: 994-1015.CrossRef
35.
Hagiwara S, Kudo M, Ueshima K, Chung H, Yamaguchi M, Takita M, Haji S, Kimura M, Arao T, Nishio K, Park A, Munakata H: The cancer stem cell marker CD133 is a predictor of the effectiveness of S1+ pegylated interferon alpha-2b therapy against advanced hepatocellular carcinoma. J Gastroenterol. 2010, 46: 212-221.CrossRefPubMed
36.
Su W, Liu W, Cheng C, Chou Y, Hung K, Huang W, Wu C, Li Y, Shiau A, Lai M: Ribavirin enhances interferon signaling via stimulation of mTOR and p53 activities. FEBS Lett. 2009, 583: 2793-2798. 10.1016/j.febslet.2009.07.027.CrossRefPubMed
37.
García A, Morales P, Rafter J, Haza A: N-Nitrosopiperidine and N-Nitrosodibutylamine induce apoptosis in HepG2 cells via the caspase dependent pathway. Cell Biol Int. 2009, 33: 1280-1286. 10.1016/j.cellbi.2009.08.015.CrossRefPubMed
38.
Chen L, Zhang Q, Chang W, Du Y, Zhang H, Cao G: Viral and host inflammation-related factors that can predict the prognosis of hepatocellular carcinoma. Eur J Cancer. 2012,  -
39.
Ceballos MP, Parody JP, Alvarez ML, Ingaramo PI, Carnovale CE, Carrillo MC: Interferon-α2b and transforming growth factor-β1 treatments on HCC cell lines: Are Wnt/β-catenin pathway and Smads signaling connected in hepatocellular carcinoma?. Biochem Pharmacol. 2011, 82: 1682-1691. 10.1016/j.bcp.2011.08.001.CrossRefPubMed
40.
Thompson MD, Dar MJ, Monga SP: Pegylated interferon alpha targets Wnt signaling by inducing nuclear export of β-catenin. J Hepatol. 2011, 54: 506-512. 10.1016/j.jhep.2010.07.020.PubMedCentralCrossRefPubMed
41.
North TE, Babu IR, Vedder LM, Lord AM, Wishnok JS, Tannenbaum SR, Zon LI, Goessling W: PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury. Proc Natl Acad Sci U S A. 2010, 107: 17315-17320. 10.1073/pnas.1008209107.PubMedCentralCrossRefPubMed
42.
Zhou M, Gu L, Zhu N, Woods W, Findley H: Transfection of a dominant-negative mutant NF-kB inhibitor (IkBm) represses p53-dependent apoptosis in acute lymphoblastic leukemia cells: interaction of IkBm and p53. Oncogene. 2003, 22: 8137-8144. 10.1038/sj.onc.1206911.CrossRefPubMed
43.
44.
Jost P, Ruland J: Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood. 2007, 109: 2700-2707.PubMed
45.
Li J, Tu H, Dai G, Dai Y, Wu Q, Shi Q, Cao Q, Li Z: N-acetyl cysteine inhibits human signet ring cell gastric cancer cell line (SJ-89) cell growth by inducing apoptosis and DNA synthesis arrest. Eur J Gastroenterol Hepatol. 2007, 19: 769-774. 10.1097/MEG.0b013e3282202bda.CrossRefPubMed
46.
Kim K, Rhim T, Choi I, Kim S: N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity. J Biol Chem. 2001, 276: 40591-40598. 10.1074/jbc.M100975200.CrossRefPubMed
47.
Chen GQY, Yao J, Jiang Q, Lin X, Chen F, Lin F, Lin M, Lin L, Zhu P: Construction of NF-kappaB-targeting RNAi adenovirus vector and the effect of NF-kappaB pathway on proliferation and apoptosis of vascular endothelial cells. Mol Bio Rep. 2010, 38: 3089-3094.CrossRef
48.
Schubert S, Neeman I, Resnick N: A novel mechanism for the inhibition of NF-kappaB activation in vascular endothelial cells by natural antioxidants. FASEB J. 2002, 16: 1931-1933.PubMed
49.
Vercelino R, Crespo I, de Souza G, Cuevas M, de Oliveira M, Marroni N, González-Gallego J, Tuñón M: S-nitroso-N-acetylcysteine attenuates liver fibrosis in cirrhotic rats. J Mol Med. 2010, 88: 401-411. 10.1007/s00109-009-0577-6.CrossRefPubMed
50.
Havre P, O’Reilly S, McCormick J, Brash D: Transformed and tumor-derived human cells exhibit preferential sensitivity to the thiol antioxidants, N-acetyl cysteine and penicillamine. Cancer Res. 2002, 62: 1443-1449.PubMed
51.
Ohata K, Ichikawa T, Nakao K, Shigeno M, Nishimura D, Ishikawa H, Hamasaki K, Eguchi K: Interferon alpha inhibits the nuclear factor kappa B activation triggered by X gene product of hepatitis B virus in human hepatoma cells. FEBS Lett. 2003, 553: 304-308. 10.1016/S0014-5793(03)01034-2.CrossRefPubMed
52.
Alexopoulou L, Holt A, Medzhitov R, Flavell R: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001, 413: 732-738. 10.1038/35099560.CrossRefPubMed
53.
Manna S, Mukhopadhyay A, Aggarwal B: IFN-alpha suppresses activation of nuclear transcription factors NF-kappa B and activator protein 1 and potentiates TNF-induced apoptosis. J Immunol. 2000, 165: 4927-4934.CrossRefPubMed
54.
Bassères D, Baldwin A: Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene. 2006, 25: 6817-6830. 10.1038/sj.onc.1209942.CrossRefPubMed
Metadata
Title
N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells
Authors
Nelson Alexandre Kretzmann
Eduardo Chiela
Ursula Matte
Norma Marroni
Claudio Augusto Marroni
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Comparative Hepatology / Issue 1/2012
Electronic ISSN: 1476-5926
DOI
https://doi.org/10.1186/1476-5926-11-4

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