Liver Protective Effects of Renin-Angiotensin System Inhibition Have No Survival Benefits in Hepatocellular Carcinoma Induced By Repetitive Administration of Diethylnitrosamine in Mice
DOI:
https://doi.org/10.3889/oamjms.2018.167Keywords:
diethylnitrosamine, hepatocellular carcinoma, renin-angiotensin system, survival analysisAbstract
BACKGROUND: Preclinical studies have demonstrated that renin-angiotensin system (RAS) signalling has strong tumour-promoting effects and RAS inhibition was associated with improvement in the overall survival in some cancer types including hepatocellular carcinoma (HCC).
OBJECTIVE: We aimed to investigate the effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) on the survival of mice with diethylnitrosamine (DEN) induced HCC.
METHODS: HCC was induced by weekly i.p. administration of DEN. Mice were treated with sorafenib (SO) (30 mg/kg), perindopril (PE) (1 mg/kg), fosinopril (FO) (2 mg/kg), losartan (LO) (10 mg/kg), PE (1 mg/kg) + SO (30 mg/kg), FO (2 mg/kg) + SO (30 mg/kg), or LO (10 mg/kg) + SO (30 mg/kg). Survival analysis was done using the Kaplan-Meier method, and the log-rank test was used for assessing the significance of difference between groups.
RESULTS: The administration of PE, FO and LO as monotherapy or as combined with SO resulted in marked improvement in the liver histologic picture with no impact on overall survival of mice.
CONCLUSION: Interfering the RAS either through the inhibition of ACE or the blockade of angiotensin II type 1 (AT1) receptors has similar effects on the liver of DEN-induced HCC mice and is not associated with longer survival due to detrimental effects of DEN on other organs. Hence, repetitive administration of DEN in such models of HCC is not suitable for mortality assessment studies.Downloads
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Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012; 379(9822): 1245-55. https://doi.org/10.1016/S0140-6736(11)61347-0
Torre LA, Bray F, Siegel RL, Ferlay J, Lortetâ€Tieulent J, Jemal A. Global cancer statistics, 2012. CA: a cancer journal for clinicians. 2015; 65(2):87-108. https://doi.org/10.3322/caac.21262
Dhanasekaran R, Bandoh S, Roberts LR. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Research. 2016;5. https://doi.org/10.12688/f1000research.6946.1
Shlomai A, de Jong YP, Rice CM. Virus associated malignancies: the role of viral hepatitis in hepatocellular carcinoma. InSeminars in cancer biology 2014; 26:78-88. https://doi.org/10.1016/j.semcancer.2014.01.004 PMid:24457013 PMCid:PMC4048791
Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. Journal of hepatology. 2012; 56(6):1384-91. https://doi.org/10.1016/j.jhep.2011.10.027 PMid:22326465
Pinter M, Trauner M, Peck-Radosavljevic M, Sieghart W. Cancer and liver cirrhosis: implications on prognosis and management. Esmo Open. 2016; 1(2):e000042. https://doi.org/10.1136/esmoopen-2016-000042 PMid:27843598 PMCid:PMC5070280
European Association For The Study Of The Liver. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. Journal of hepatology. 2012; 56(4):908-43. https://doi.org/10.1016/j.jhep.2011.12.001 PMid:22424438
Di Marco V, De Vita F, Koskinas J, Semela D, Toniutto P, Verslype C. Sorafenib: from literature to clinical practice. Annals of oncology. 2013; 24(suppl_2):ii30-7.
Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011; 140(5): 1410-26. https://doi.org/10.1053/j.gastro.2011.03.006 PMid:21406195 PMCid:PMC3682501
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M. Sorafenib in advanced hepatocellular carcinoma. New England journal of medicine. 2008; 359(4):378-90. https://doi.org/10.1056/NEJMoa0708857 PMid:18650514
Bruix J, Merle P, Granito A, Huang YH, Bodoky G, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross Paul J. LBA-03 Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Annals of Oncology. 2016; 27(suppl_2):ii140-1.
Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clinical cancer research. 2014; 20(8):2072-9. https://doi.org/10.1158/1078-0432.CCR-13-0547 PMid:24589894
Facciorusso A, Del Prete V, Crucinio N, Muscatiello N, Carr BI, Di Leo A, Barone M. Angiotensin receptor blockers improve survival outcomes after radiofrequency ablation in hepatocarcinoma patients. Journal of gastroenterology and hepatology. 2015; 30(11):1643-50. https://doi.org/10.1111/jgh.12988 PMid:25974743
De Paepe B, Verstraeten VL, De Potter CR, Bullock GR. Increased angiotensin II type-2 receptor density in hyperplasia, DCIS and invasive carcinoma of the breast is paralleled with increased iNOS expression. Histochemistry and cell biology. 2002; 117(1):13-9. https://doi.org/10.1007/s00418-001-0356-0 PMid:11819093
Chae YK, Valsecchi ME, Kim J, Bianchi AL, Khemasuwan D, Desai A, Tester W. Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer investigation. 2011; 29(9):585-93. https://doi.org/10.3109/07357907.2011.616252 PMid:21936625
Sjöberg T, RodrÃguez LA, Lindblad M. Angiotensin-converting enzyme inhibitors and risk of esophageal and gastric cancer: a nested case-control study. Clinical Gastroenterology and Hepatology. 2007; 5(10):1160-6. https://doi.org/10.1016/j.cgh.2007.08.005 PMid:17916544
Christian JB, Lapane KL, Hume AL, Eaton CB, Weinstock MA. Association of ACE inhibitors and angiotensin receptor blockers with keratinocyte cancer prevention in the randomized VATTC trial. Journal of the National Cancer Institute. 2008; 100(17):1223-32. https://doi.org/10.1093/jnci/djn262 PMid:18728281
Morris ZS, Saha S, Magnuson WJ, Morris BA, Borkenhagen JF, Ching A, Hirose G, McMurry V, Francis DM, Harari PM, Chappell R. Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensinâ€converting enzyme inhibitors or angiotensin receptor blockers. Cancer. 2016; 122(16):2487-95. https://doi.org/10.1002/cncr.30079 PMid:27203227 PMCid:PMC4998053
Keizman D, Huang P, Eisenberger MA, Pili R, Kim JJ, Antonarakis ES, Hammers H, Carducci MA. Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. European journal of cancer. 2011; 47(13):1955-61. https://doi.org/10.1016/j.ejca.2011.04.019 PMid:21600760 PMCid:PMC3175366
Menter AR, Carroll NM, Sakoda LC, Delate T, Hornbrook MC, Jain RK, Kushi LH, Quinn VP, Ritzwoller DP. Effect of angiotensin system inhibitors on survival in patients receiving chemotherapy for advanced non–small-cell lung cancer. Clinical lung cancer. 2017; 18(2):189-97. https://doi.org/10.1016/j.cllc.2016.07.008 PMid:27637408 PMCid:PMC5424707
Kuczynski EA, Lee CR, Man S, Chen E, Kerbel RS. Effects of sorafenib dose on acquired reversible resistance and toxicity in hepatocellular carcinoma. Cancer research. 2015; 75(12):2510-9. https://doi.org/10.1158/0008-5472.CAN-14-3687 PMid:25908587
Abd-Alhaseeb MM, Zaitone SA, Abou-El-Ela SH, Moustafa YM. Olmesartan Potentiates the Anti-Angiogenic Effect of Sorafenib in Mice Bearing Ehrlich's Ascites Carcinoma: Role of Angiotensin (1–7). PLoS One. 2014; 9(1):e85891. https://doi.org/10.1371/journal.pone.0085891 PMid:24465768 PMCid:PMC3899087
Tang TC, Man S, Xu P, Francia G, Hashimoto K, Emmenegger U, Kerbel RS. Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia. 2010; 12(11):928-40. https://doi.org/10.1593/neo.10804 PMid:21076618 PMCid:PMC2978915
Freireich EJ, Gehan EA, Rall D, Schmidt LH, Skipper HE. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer chemotherapy reports. 1966; 50(4):219. PMid:4957125
Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. World Health Organization; 2010.
Fujita M, Hayashi I, Yamashina S, Fukamizu A, Itoman M, Majima M. Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth. Carcinogenesis. 2005; 26(2):271-9. https://doi.org/10.1093/carcin/bgh324 PMid:15637093
Tamarat R, Silvestre JS, Durie M, Levy BI. Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor-and inflammation-related pathways. Laboratory investigation. 2002; 82(6):747. https://doi.org/10.1097/01.LAB.0000017372.76297.EB PMid:12065685
Rosenthal T, Gavras I. Angiotensin inhibition and malignancies: a review. Journal of human hypertension. 2009; 23(10):623. https://doi.org/10.1038/jhh.2009.21 PMid:19339998
Pinter M, Weinmann A, Wörns MA, Hucke F, Bota S, Marquardt JU, Duda DG, Jain RK, Galle PR, Trauner M, Peck-Radosavljevic M. Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United European gastroenterology journal. 2017; 5(7):987-96. https://doi.org/10.1177/2050640617695698 PMid:29163965 PMCid:PMC5676550
Aydiner A, Ciftci R, Sen F. Renin-Angiotensin system blockers may prolong survival of metastatic non-small cell lung cancer patients receiving erlotinib. Medicine. 2015; 94(22). https://doi.org/10.1097/MD.0000000000000887
Fabris B, Yamada H, Cubela R, Jackson B, Mendelsohn FA, Johnston CI. Characterization of cardiac angiotensin converting enzyme (ACE) and in vivo inhibition following oral quinapril to rats. British journal of pharmacology. 1990; 100(3):651-5. https://doi.org/10.1111/j.1476-5381.1990.tb15862.x PMid:2167741 PMCid:PMC1917808
Sauer WH, Baer JT, Berlin JA, Kimmel SE. Class effect of angiotensin-converting enzyme inhibitors on prevention of myocardial infarction. American Journal of Cardiology. 2004; 94(9):1171-3. https://doi.org/10.1016/j.amjcard.2004.07.087 PMid:15518614
Furberg CD, Herrington DM, Psaty BM. Are drugs within a class interchangeable?. The Lancet. 1999; 354(9185):1202-4. https://doi.org/10.1016/S0140-6736(99)03190-6
Lala A, McLaughlin MA. Do ACE inhibitors all provide the same outcomes benefits in high-risk cardiovascular patients?. Current hypertension reports. 2008; 10(4):286-92. https://doi.org/10.1007/s11906-008-0053-7 PMid:18625157
Binato M, Schmidt MK, Volkweis BS, Ribeiro GB, Edelweiss MI, Gurski RR. Mouse model of diethylnitrosamine-induced gastric cancer. Journal of Surgical Research. 2008; 148(2):152-7. https://doi.org/10.1016/j.jss.2007.12.748 PMid:18456281
Verna L, Whysner J, Williams GM. N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacology & therapeutics. 1996; 71(1-2):57-81. https://doi.org/10.1016/0163-7258(96)00062-9
Williams GM, Iatropoulos MJ, Jeffrey AM. Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine. Toxicologic pathology. 2000; 28(3):388-95. https://doi.org/10.1177/019262330002800306 PMid:10862555
Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK, Thorgeirsson SS. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nature genetics. 2004; 36(12):1306. https://doi.org/10.1038/ng1481 PMid:15565109
Finnberg N, Stenius U, Högberg J. Heterozygous p53-deficient (+/−) mice develop fewer p53-negative preneoplastic focal liver lesions in response to treatment with diethylnitrosamine than do wild-type (+/+) mice. Cancer letters. 2004; 207(2):149-55. https://doi.org/10.1016/j.canlet.2003.11.013 PMid:15072823
Yoshino H, Futakuchi M, Cho YM, Ogawa K, Takeshita F, Imai N, Tamano S, Shirai T. Modification of an in vivo lung metastasis model of hepatocellular carcinoma by low dose N-nitrosomorpholine and diethylnitrosamine. Clinical & experimental metastasis. 2005; 22(5):441-7. https://doi.org/10.1007/s10585-005-2807-9 PMid:16283487
Heindryckx F, Colle I, Van Vlierberghe H. Experimental mouse models for hepatocellular carcinoma research. International journal of experimental pathology. 2009; 90(4):367-86. https://doi.org/10.1111/j.1365-2613.2009.00656.x PMid:19659896 PMCid:PMC2741148
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M. Sorafenib in advanced hepatocellular carcinoma. New England journal of medicine. 2008; 359(4):378-90. https://doi.org/10.1056/NEJMoa0708857 PMid:18650514
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. The lancet oncology. 2009; 10(1):25-34. https://doi.org/10.1016/S1470-2045(08)70285-7
Schramm C, Schuch G, Lohse AW. Sorafenib-induced liver failure. The American journal of gastroenterology. 2008; 103(8):2162. https://doi.org/10.1111/j.1572-0241.2008.01982_19.x PMid:18796127
Keating GM, Santoro A. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009; 69(2):223-40. https://doi.org/10.2165/00003495-200969020-00006 PMid:19228077
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