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The Role of Isoprenoids in Liver Cancer: A Review

Explore the significance of isoprenoids in liver cancer, their tumor suppressive effects, and molecular mechanisms. Discover the etiology of liver cancer and the impact of factors like HBV, HCV, and aflatoxins. Gain insights into the incidence and molecular events contributing to liver cancer.

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The Role of Isoprenoids in Liver Cancer: A Review

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  1. The Role of Isoprenoids in Liver Cancer: A Review PRESENTED BY: DHARTI SHAH DEPARTMENT OF NUTRITION AND FOOD SCIENCES TEXAS WOMAN’S UNIVERSITY DENTON, TEXAS

  2. Most rapidly increasing cancer type • Increased incidence in developed countries • Tumor suppressive effects of isoprenoids have been shown in many cancers • A comprehensive review would provide a good insight on the use of isoprenoids in liver cancer SIGNIFICANCE OF THE STUDY

  3. Literature search was carried out using research databases • Key words: • Mevalonate pathway • Liver cancer • HBV, HCV, Aflatoxins • Molecular mechanisms in liver cancer • Isoprenoids • Farnesol • Geraniol • d-limonene, Perillyl alcohol • geranylgeraniol METHODS

  4. Cancer - second leading cause of death in U.S. • Estimated new cases and deaths in U.S. (all cancers) • 2008 – 1,437,920; 565,650 • Liver cancer – 5th most common cancer • 2007 – 19,160; 16,780 • 2008 – 21,370; 18,410 • 5 year survival rate is < 3% INTRODUCTION ACS http://www.cancer.org/docroot/CRI/content/CRI_2_2_1X_How_many_people_get_liver_cancer_25.asp?sitearea; Lencioni . et. al., Ital. J Gastroenterol, 1994

  5. Primary liver cancers (PLC) • Hepatocellular carcinoma (HCC) – hepatocytes, most common type • Cholangiocarcinoma (CCA) – cells of intrahepatic bile ducts • Global incidence • > 80% of all cases in developing countries • Increased incidence seen in developed countries LIVER CANCER Srivatanakul et. al., Asian Pacific J Cancer Prev. ,2004

  6. El-Serag et. al. confirm an increase in the number of HCC cases from 1975-1998 • Study period divided into 7 3-year periods • Age groups (20-49, 50-64, 65-74, or ≥ 75 yrs) • Results • 2-fold increase in incidence of HCC between 1975-1998 • Highest incidence seen among Asian migrants and Blacks • 25% increase during the last 3 year period – Whites affected the most • Contributing factors • HBV - Asian countries (Southeast Asia) • HCV – Black and White people • Needle sharing, drug use, blood transfusions INCIDENCE IN UNITED STATES El-Serag et. al., Intern. Med., 2003

  7. Major contributing factors • Hepatitis B (HBV) • Hepatitis C (HCV) • Aflatoxin-B1 • Minor contributing factors • Chronic alcoholism Cirrhosis HCC • Obesity Hepatic steatosis oxidative stress • Diabetes • Anabolic steroids • Toxins – arsenic, vinyl chloride ETIOLOGY OF LIVER CANCER ACS http://www.cancer.org/docroot/CRI/content/CRI_2_4_2X_What_are_the_risk_factors_for_liver_cancer_25.asp?sitearea

  8. HBV DNA fuses with cellular DNA – gene expression HEPATITIS B X protein (HBX) Tumor suppressive activity Feitelson, Hum. Pathol., 2004

  9. HCV core protein upregulates many oncogenic genes, including c-myc • Hepatic steatosis – an independent risk factor in HCC HEPATITIS C (HCV)Core protein oxidation Moriya et. al., J. Gen. Virol., 1997; Moriya et. al., Nat. Med., 1998; Ohata et. al., Cancer, 2003

  10. Viral agents and environmental carcinogens - cancer • Aflatoxin exposure ---- G to T transversion in codon 249 of p53 • HBV + aflatoxin interaction may be synergistic • Liver injury as a result of HBV is a critical factor • Increased expression of cytochrome P450’s that metabolize carcinogens Aflatoxin-B1 Wild et. al., Environ. Health Persp., 1993; Eaton and Gallagher, Annu. Rev. Pharmacol. Toxicol, 1994; Hussain et. al., Oncogene, 1994

  11. MOLECULAR EVENTS IN CANCER

  12. CARCINOGENESIS Protooncogenes Tumor suppressive genes Growth factors Malignancy Murukami, et.al., Cancer Res., 1993

  13. Hepatocytes altered phenotypically OVERVIEW OF LIVER CANCER Feitelson, Hum. Pathol., 2004; Anthony, J. Clin. Path., 1973; Thorgeirsson et. al., Nat. Genet., 2002

  14. c-myc transcription factor cell growth • Early event in hepatocarcinogenesis • Hypomethylation of c-myc • c-myc transgenic mice • Dysplastic changes – 2 months, well developed HCC – 15-18 months • TGF-α active liver regeneration • Tumor progression • TGF-α transgenic mice • Multifocal, well differentiated HCC – 10-15 months Protooncogenes and growth factors Bhave et.al., Carcinogenesis, 1988; Sandgren et.al.,Oncogene,1989

  15. Dysplastic changes in hepatocytes • Apoptosis of healthy liver cells Co-expression (c-myc-TGF-α) phosphorylated forms of ras and phosphoinositol-3 kinase IĸB kinase (phosphorylated) Nuclear factor κB Apoptosis Murukami et.al.,Cancer Res.,1993; Factor et.al.,Hepatology,2001

  16. Overexpression of TGF-β1 or c-myc/TGF-β1 • sensitivity of cells to TGFβ1 • Overexpression of c-myc and loss of TGF-β II receptors • HBV X and HCV core protein interfere with function of TGF-β1 • Hedgehog pathway • Cell differentiation • expression of two target genes • PTCH1 and Gli1 C-myc-TGF-β1 and Hedgehog pathway Alexandrow et.al.,Cancer Res.,1995; Fynn et.al.,Crit.Rev.Oncog.,1993; Tsuchihara et.al.,Virology,1999; Huang et.al.,Carcinogenesis,2006

  17. Carcinogens, viruses, growth factors Nuclear factor-κB (NF-κB) DNA damage Proapoptotic genes NF-κB Anti-apoptotic genes α-fetoprotein (AFP) TNF-α Cell survival Arsura and Cavin,Cancer Lett.,2005

  18. Rel/NF-κB (cytoplasm) transcription factors • Role studied in HBV positive Hep 3B cells NF-κB’s role in liver cancer Rel/NF-κB IκBα (phosphorylated) IĸBα TGF-α releases Rel/NF-κB (cytoplasm) Rel/NF-κB (nucleus) cell survival Chiao et.al.,Cancer,2002

  19. c-Jun component of activator protein 1 (AP-1) • Cell survival, cell cycle progression • After initiation stage of tumor development • Oncogenic activity of c-Jun • N-terminal phosphorylation • Interaction with Ras • Suppression of p53 • TNF-α induced NF-κB activity c-Jun Johnson et. al., Mol. Cell Biol., 1996; Eferl et. al., J. Cell Biol., 1999; Eferl et.al., Cell, 2003; Schreiber et. al., Genes Dev., 1999

  20. Multistep and a well coordinated process • Vascular endothelium specific angiogenic factors Angiogenesis Vascular endothelial growth factors (VEGF) Angiopoietin family Ephrin family Endothelium Hypoxia inducible factor 1α Interleukin-6,8 Angiogenesis Rac NF-κB Yancopoulas et. al., Nature, 2000; Arsura and Cavin, Cancer lett, 2005; Lee et.al., Clin. Cancer Res., 2006

  21. Acetyl CoA MEVALONATE PATHWAY IN NORMAL CELLS HMG CoA HMG CoA reductase Mevalonate Isopentenyl-PP isomerase Dimethylallyl-PP Isopentenyl-5-PP Geranyl-PP Cholesterol Farnesol FTase Protein prenylation Ras, lamin B Farnesyl-PP Cell growth Brown and Goldstein,Nature,1990; Goldstein et.al.,Cell,2006

  22. SREBP pathway

  23. Acetyl CoA MEVALONATE PATHWAY IN NORMAL CELLS HMG CoA HMG CoA reductase Mevalonate Isopentenyl-PP isomerase Dimethylallyl-PP Isopentenyl-5-PP Geranyl-PP Cholesterol Farnesol FTase Protein prenylation Ras, lamin B Farnesyl-PP Cell growth Brown and Goldstein,Nature,1990; Goldstein et.al.,Cell,2006

  24. Acetyl CoA MEVALONATE PATHWAY IN CANCER CELLS HMG CoA HMG CoA reductase Mevalonate Isopentenyl-PP isomerase Dimethylallyl-PP Isopentenyl-5-PP Geranyl-PP Cholesterol Farnesol FTase Protein prenylation Ras, lamin B Farnesyl-PP Cell growth Brown and Goldstein,Nature,1990; Goldstein et.al.,Cell,2006

  25. Reductase lacks active site or no conformational change occurs • Hypomethylation of reductase gene • Mutation in SCAP protein • Transition at one of the codons of SCAP • Increase in active form of HMG CoA reductase • Altered enzyme kinase - phosphatase system DYSREGULATED PATHWAY Siperstein and Fagan,Cancer Res.,1964; Vasudevan et.al.,FASEB J.,1994; Goldstein et.al.,Cell,2006; Kawata et.al.,Cancer Res.,1990

  26. Acetyl CoA Reductase regulation in Hep G2 cells Compactin Enzyme activity HMG CoA HMG CoA reductase Mevalonate Isopentenyl-5-PP Enzyme mRNA content Geranyl-PP Cholesterol Farnesol Farnesyl-PP U18666A Cohen and Griffioen, Biochem. J.,1998

  27. Secondary metabolites of mevalonate metabolism in plants • Five carbon isoprene units ISOPRENOIDS AND CANCER ISOPRENOIDS Pure Mixed • Monoterpenes – d-imonene (orange peel oil), Perillyl alcohol (lavender, cherries), Geraniol (berries) • Diterpenes – Geranylgeraniol • Sesquiterpenes – Farnesol • Isoflavones • Tocotrienols • (vegetable oils, whole grains) Blocking and suppressing agents Elson and Yu, J. Nutr.,1994; Elson et. al., Proc. Soc.Exp.Biol.Med., 1999

  28. Isoprenoids • Cell cycle arrest • Apoptosis • Degradation of HMG-CoA reductase • Anti-angiogenic • Inhibition of protein isoprenylation Mechanism of action

  29. Perillyl alcohol (POH), d-limonene, geraniol CELL CYCLE ARREST G1 Cyclin/cdk complex c-myc S DNA replication Mitosis M G2 Mo and Elson, Nutritional Oncology, 2006; Clark, Oncology, 2006; Packham and Cleaveland, Mol. Cell Biol., 1994

  30. Geranylgeraniol (GGOH), Perillyl alcohol (POH) APOPTOSIS Proapoptotic proteins (Bad, Bax) Caspase activity Apoptosis Anti-apoptotic proteins (Bcl-2, Bcl-XL) Masuda et.al., Leuk. Res., 2000

  31. Acetyl CoA HMG CoA reductase inhibitors HMG CoA HMG CoA reductase Geranylgeraniol Degradation Mevalonate Translation Geranylgeranyl-PP Geranyl-PP Farnesol Farnesol d-limonene Farnesyl-PP Perillyl alcohol Cholesterol FTase Degradation Protein prenylation Ras, lamin B Translation Cell growth Crowell et.al., J. Biol. Chem., 1991; Hohl and Lewis, J. Biol. Chem., 1995; Keller et.al., Arch. Biochem. Biophys., 1996

  32. Perillyl alcohol (POH) • mannose-6-phosphate/insulin growth factor II receptor • TGF-β type I, II and III receptors in tumor cells Monoterpenes diethylnitrosamine (DEN) 1 month – induced liver tumors Male Fischer rats POH treated (n=10) Control (n=11) • 1% w/w POH – 1st week • 2% w/w POH – 19 weeks (Powdered diet) 7.0g Mean tumor mass 0.8g 5-fold – large tumors 10-fold – small tumors Apoptotic index Low High Mills et.al., Cancer Res., 1995

  33. Anti-angiogenic function – Perillyl alcohol (POH) • Rac – changes in cell morphology • POH inhibits Rac interaction with membranes • p21 activated kinase – cell migration • Angiogenic factors • VEGF – cell migration and cell survival • POH decreases release of VEGF, increases Ang2 • Ang2 – neovascularization ANTI-ANGIOGENIC ROLE Capillary formation Blood vessel formation Loutari et.al., J. Pharmacol. Exp. Ther., 2004; Connolly et.al., Mol. Biol. Cell, 2002

  34. d-limonene • Mechanism - Apoptosis and decreased cell proliferation Monoterpenes N-nitrosomorpholine (NNM) 8 weeks Sprague-Dawley rats Group 1 (n=20) Chow pellets Group 2 (n=20) Chow pellets + 1% d-limonene Group 3 (n=60) Chow pellets + 2% d-limonene GST-P positive foci and lesions Apoptotic index Membrane associated p21 ras No significant effects Kaji et. al., Int. J. Cancer, 2001

  35. Geraniol • Results • Tumor volumes in experimental rats was 20% that of control rats • Mechanism • Apoptosis Morris 7777 hepatomas Male buffalo rats Monoterpenes • Diet – 14 days before and 42 days after tumor transplant • Control (n=6) • AIN-76A • Experimental • (AIN-76A + geraniol 350μmol/d) Yu et.al., J. Nutr., 1995

  36. GGOH (1-50μmol/L) Bcl-XL Diterpenes – Geranylgeraniol (GGOH)HuH-7 cells BH3 domain Caspase-8 Bid + Bax - COOH CAD ICAD Caspase-3 cleaves Caspase-9 Nucleus Cytochrome-c apaf1 DNA fragmentation Takeda et. al., Jpn. J. Cancer Res., 2001; Enari et. al., Nature, 1998; Wang et. al., Genes &Dev., 1996; Luo et. al., Cell, 1998

  37. Farnesol • Mechanism - FOH – inhibited HMG CoA reductase; GOH induced apoptosis Initiated – DEN, 2-AAF Male Wistar rats Sesquiterpenes Corn oil( n=12) 0.25 ml/100g GOH (n=12) 25mg/100g FOH (n=12) 25mg/100g Incidence + number of nodules Mean area of PNL’s % liver section Occupied by PNL’s Apoptosis Ong et.al., Carcinogenesis, 2006

  38. In vivo • In vitro Hep G2 cells C3H/He – spontaneous liver tumor MIXED ISOPRENOIDSTocotrienols Control Experimental DMSO γ, δ isoforms (3 days) conc. of δ isoforms 72 hours Control (n=17) Experimental (n=14) T3 mixture (2.25mg/d) γ, α, δ Reduced cell viability apoptosis 7.6 tumors/mouse 1.4 tumors/mouse 100 µM – 4 hours IC50 conc. – γ – 27.4µM δ – 9.6 µM S-phase arrest Anti-carcinogenic effect Cell proliferation

  39. Contain a farnesol or geraniol molecule • More potent • Geranylgaranoic acid (GGA) • 4,5 didehydro GGA SYNTHETIC ISOPRENOIDS Mo and Elson, Exp. Biol. Med., 2004

  40. Geranylgeranoic acid 10 µM SYNTHETIC ISOPRENOIDSHuH-7 cells TGF-α + EGF Interleukin-1-β converting enzyme Cysteine protease precursor 32 APOPTOSIS Shidoji et. al., Biochem. Biophys. Res. Commun., 1997; Enari et. al., Nature, 1996; Nakamura et. al., Biochem. Biophys. Res. Commun., 1996

  41. Isoprenoids in liver cancer • Liver tumor regression achieved chiefly by apoptosis • Decrease cell proliferation and tumor growth • Inhibition of protein isoprenylation • Degradation of reductase SUMMARY

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