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Oxidative Stress in Hepatocarcinogenesis and Role of Antioxidant Therapy

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Handbook of Oxidative Stress in Cancer: Mechanistic Aspects

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Abstract

Oxidative stress plays important roles in hepatocarcinogenesis and subsequent progression of hepatocytes to hepatocellular carcinoma (HCC) phenotype (Warburg effect) where glucose is converted into lactate. In previous publications, we declared that pyruvate is a strong antioxidant formed from cytoplasmic glucose oxidation (glycolysis) in normal cellular metabolism that is distinguished from lactate (not antioxidant) formed during cancer metabolism. Lactate increases endogenous oxidative stress and favors generation of reactive oxygen species (ROS). Subsequent ROS-induced genotoxic effects increase mutagenesis and tumorigenesis. Hepatitis viruses, chronic alcohol consumption, and hepatotoxins are causes of hepatitis increasing ROS production and favoring hepatocarcinogenesis, invasion, and metastasis. Inflammatory mediators and cytokines are common in hepatocarcinogenesis, fibrogenesis, and insulin resistance. Remedies of prophetic medicine are natural products and medicinal plants that are rich in many active ingredients all of which are antioxidants, e.g., thymoquinone (of Nigella sativa), anethol (of fennel), dehydrocostus lactone and costunolide (of costus, Saussurea lappa), flavonoids (of natural honey and ajwa date fruit), and others. In this chapter, Ajwa date fruit extract caused exciting reversion of malignant cells into normal behavior that was reported in study done in Saudi Arabia. β-D-glucan (in Ajwa dates) causes a dose- and time-dependent inhibition of HCC cells viability and growth. Natural honey suppresses TNF-α that mediates tumor initiation, promotion, and progression. Natural antioxidant ingredients in Nigella sativa protect liver cells against malignant transformation via different mechanisms, e.g., suppressing oxidative stress-induced tissue damage. Nigella sativa includes thymoquinone, thymol, and α-hederin exert potent antioxidant effects. Thymoquinone, thymol, and alpha-hederin protect liver cells from a wide range of injurious agents. Costus enhanced the protein levels of many proapoptotic factors and suppressed the protein levels of antiapoptotic factors. Fennel exerts antimutagenic effects. Essential oil of fennel exerts potent protective effects against chemotherapy-induced genotoxicity in experimental animals.

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References

  • Ahmed S, Othman NH (2013) Honey as a potential natural anticancer agent: a review of its mechanisms. Evid Based Complement Alternat Med 2013:1–7

    Article  Google Scholar 

  • Ait Mbarek L, Ait Mouse H, Elabbadi N, Bensalah M, Gamouh A, Aboufatima R et al (2007) Anti-tumor properties of blackseed (Nigella sativa L.) extracts. Braz J Med Biol Res 40(6):839–847

    Article  CAS  PubMed  Google Scholar 

  • Badgujar SB, Patel VV, Bandivdekar AH (2014) Foeniculum vulgare mill: a review of its botany, phytochemistry, pharmacology, contemporary application, and toxicology. Biomed Res Int 2014:1–33

    Article  Google Scholar 

  • Bai T, Lian L-H, Wu Y-L, Wan Y, Nan J-X (2013) Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells. Int Immunopharmacol 15(2):275–281

    Article  CAS  PubMed  Google Scholar 

  • Block G, Patterson B, Subar A (1992) Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 18(1):1–29

    Article  CAS  PubMed  Google Scholar 

  • Byambaragchaa M, de la Cruz J, Yang SH, Hwang S-G (2013) Anti-metastatic potential of ethanol extract of Saussurea involucrata against hepatic cancer in vitro. Asian Pac J Cancer Prev 14(9):5397–5402

    Article  PubMed  Google Scholar 

  • Calado RT, Brudno J, Mehta P, Kovacs JJ, Wu C, Zago MA et al (2011) Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 53(5):1600–1607

    Article  CAS  PubMed  Google Scholar 

  • Cederbaum A (1991) Microsomal generation of reactive oxygen species and their possible role in alcohol hepatotoxicity. Alcohol Alcohol (Oxford, Oxfordshire) 1(Supplement):291–296

    CAS  Google Scholar 

  • Dejean A (1990) Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma. Mol Biol Med 7(3):213–222

    CAS  PubMed  Google Scholar 

  • Eid N, Enani S, Walton G, Corona G, Costabile A, Gibson G et al (2014) The impact of date palm fruits and their component polyphenols, on gut microbial ecology, bacterial metabolites and colon cancer cell proliferation. J Nutri Sci 3:1–9

    Google Scholar 

  • El Sayed SM, Mahmoud AA, El Sawy SA, Abdelaal EA, Fouad AM, Yousif RS et al (2013) Warburg effect increases steady-state ROS condition in cancer cells through decreasing their antioxidant capacities (anticancer effects of 3-bromopyruvate through antagonizing Warburg effect). Med Hypotheses 81(5):866–870

    Article  PubMed  Google Scholar 

  • Guyton K, Kensler TW (1993) Oxidative mechanisms in carcinogenesis. Br Med Bull 49(3):523–544

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B (2007) Oxidative stress and cancer: have we moved forward? Biochem J 401(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Jaeschke H, Mitchell JR (1989) Mitochondria and xanthine oxidase both generate reactive oxygen species in isolated perfused rat liver after hypoxic injury. Biochem Biophys Res Commun 160(1):140–147

    Article  CAS  PubMed  Google Scholar 

  • Jain SK, Pemberton PW, Smith A, McMahon RF, Burrows PC, Aboutwerat A, Warnes TW (2002) Oxidative stress in chronic hepatitis C: not just a feature of late stage disease. J Hepatol 36(6):805–811

    Article  CAS  PubMed  Google Scholar 

  • Jüngst C, Cheng B, Gehrke R, Schmitz V, Nischalke HD, Ramakers J et al (2004) Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 39(6):1663–1672

    Article  PubMed  Google Scholar 

  • Khan A, Chen H, Tania M, Zhang DZ (2011) Anticancer activities of Nigella sativa (black cumin). Afr J Tradit Complement Altern Med 8(5S):226–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan F, Khan TJ, Kalamegam G, Pushparaj PN, Chaudhary A, Abuzenadah A et al (2017) Anti-cancer effects of Ajwa dates (Phoenix dactylifera L.) in diethylnitrosamine induced hepatocellular carcinoma in Wistar rats. BMC Complement Altern Med 17(1):1–10

    Article  Google Scholar 

  • Kuchino Y, Mori F, Kasai H, Inoue H, Iwai S, Miura K et al (1987) Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature 327(6117):77–79

    Article  CAS  PubMed  Google Scholar 

  • Kumar P, Patra AK, Mandal GP, Samanta I, Pradhan S (2017) Effect of black cumin seeds on growth performance, nutrient utilization, immunity, gut health and nitrogen excretion in broiler chickens. J Sci Food Agric 97(11):3742–3751

    Article  CAS  PubMed  Google Scholar 

  • Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y et al (2002) Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 122(2):352–365

    Article  CAS  PubMed  Google Scholar 

  • Lin X, Peng Z, Fu X, Liu C, Xu Y, Ji W et al (2016) Volatile oil from Saussurea lappa exerts antitumor efficacy by inhibiting epithelial growth factor receptor tyrosine kinase-mediated signaling pathway in hepatocellular carcinoma. Oncotarget 7(48):79761

    Article  PubMed  PubMed Central  Google Scholar 

  • Loeppky RN (1994) Nitrosamine and N-nitroso compound chemistry and biochemistry: advances and perspectives: ACS publications. Chapter 1:1–18

    Google Scholar 

  • Machida K, Cheng KT-N, Sung VM-H, Shimodaira S, Lindsay KL, Levine AM et al (2004) Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci 101(12):4262–4267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malik AN, Czajka A (2013) Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13(5):481–492

    Article  CAS  PubMed  Google Scholar 

  • Matsuzawa-Nagata N, Takamura T, Ando H, Nakamura S, Kurita S, Misu H et al (2008) Increased oxidative stress precedes the onset of high-fat diet–induced insulin resistance and obesity. Metabolism 57(8):1071–1077

    Article  CAS  PubMed  Google Scholar 

  • Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H et al (2001) Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 61(11):4365–4370

    CAS  PubMed  Google Scholar 

  • Nair SV, Hettihewa M, Rupasinghe H (2014) Apoptotic and inhibitory effects on cell proliferation of hepatocellular carcinoma HepG2 cells by methanol leaf extract of Costus speciosus. Biomed Res Int 2014:1–10

    Google Scholar 

  • Neethu P, Suthindhiran K, Jayasri M (2017) Methanolic extract of Costus pictus D. DON induces cytotoxicity in liver hepatocellular carcinoma cells mediated by histone deacetylase inhibition. Pharmacogn Mag 13(Suppl 3):s533–s538

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ozen C, Yildiz G, Dagcan AT, Cevik D, Ors A, Keles U et al (2013) Genetics and epigenetics of liver cancer. New Biotechnol 30(4):381–384

    Article  CAS  Google Scholar 

  • Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11):2913–2921

    Article  CAS  PubMed  Google Scholar 

  • Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182(3):311–322

    Article  CAS  PubMed  Google Scholar 

  • Schwartz JD, Schwartz M, Mandeli J, Sung M (2002) Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol 3(10):593–603

    Article  PubMed  Google Scholar 

  • Severi T, Van Malenstein H, Verslype C, Van Pelt JF (2010) Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets. Acta Pharmacol Sin 31(11):1409–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shati AA, Alkahtani MA, Alfaifi MY, Elbehairi SEI, Elsaid FG, Prasanna R, Mir MA (2020) Secondary metabolites of Saussurea costus leaf extract induce apoptosis in breast, liver, and colon cancer cells by Caspase-3-dependent intrinsic pathway. BioMed Res Int 20:1–11

    Google Scholar 

  • Subasinghe H, Hettihewa L, Gunawardena S, Liyanage T (2014) Methanol and water extracts of Costus speciosus (j. könig) sm. leaves reverse the high-fat-diet induced peripheral insulin resistance in experimental Wistar rats. Int Res J Pharm 5(2):44–49

    Article  Google Scholar 

  • Sumida Y, Nakashima T, Yoh T, Nakajima Y, Ishikawa H, Mitsuyoshi H et al (2000) Serum thioredoxin levels as an indicator of oxidative stress in patients with hepatitis C virus infection. J Hepatol 33(4):616–622

    Article  CAS  PubMed  Google Scholar 

  • Tabassum H, Ahmad A, Ahmad IZ (2018) Nigella sativa L. and its bioactive constituents as Hepatoprotectant: a review. Curr Pharm Biotechnol 19(1):43–67

    Article  CAS  PubMed  Google Scholar 

  • VanderVeen LA, Hashim MF, Nechev LV, Harris TM, Harris CM, Marnett LJ (2001) Evaluation of the mutagenic potential of the principal DNA adduct of acrolein. J Biol Chem 276(12):9066–9070

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Li Z, Ye Y, Xie L, Li W (2016) Oxidative stress and liver cancer: etiology and therapeutic targets. Oxidative Med Cell Longev 1–9

    Google Scholar 

  • Xu F, Yan J-J, Gan Y, Chang Y, Wang H-L, He X-X, Zhao Q (2019) miR-885-5p negatively regulates Warburg effect by silencing hexokinase 2 in liver cancer. Mol Ther Nucleic Acids 18:308–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yasin BR, El-Fawal HA, Mousa SA (2015) Date (Phoenix dactylifera) polyphenolics and other bioactive compounds: a traditional Islamic remedy’s potential in prevention of cell damage, cancer therapeutics and beyond. Int J Mol Sci 16(12):30075–30090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng Z, Feng W, Zhuo L (2008) Influence of electroacupuncture on cytochrome P450 2E1 expression, oxidation, anti-oxidation in non-alcoholic fatty liver tissue. J Fourth Military Medical University 29(11):994–997

    CAS  Google Scholar 

  • Zihlif MA, Mahmoud IS, Ghanim MT, Zreikat MS, Alrabadi N, Imraish A et al (2013) Thymoquinone efficiently inhibits the survival of EBV-infected B cells and alters EBV gene expression. Integr Cancer Ther 12(3):257–263

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

    Salah Mohamed El Sayed

  2. Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Sohag, Egypt

    Salah Mohamed El Sayed

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  1. Salah Mohamed El Sayed
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Correspondence to Salah Mohamed El Sayed .

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Editors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA

    Bimal K. Ray

  3. CSIR-Indian Institute of Chemical Biology, Kolkata, India

    Susanta Roychoudhury

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El Sayed, S.M. (2022). Oxidative Stress in Hepatocarcinogenesis and Role of Antioxidant Therapy. In: Chakraborti, S., Ray, B.K., Roychoudhury, S. (eds) Handbook of Oxidative Stress in Cancer: Mechanistic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-15-9411-3_187

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