Advertisement

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 12, pp 1591–1604 | Cite as

Telmisartan attenuates N-nitrosodiethylamine-induced hepatocellular carcinoma in mice by modulating the NF-κB-TAK1-ERK1/2 axis in the context of PPARγ agonistic activity

  • Sameh SaberEmail author
  • Ahmed E. Khodir
  • Wafaa E. Soliman
  • Mohamed M. Salama
  • Walied S. Abdo
  • Baraah Elsaeed
  • Karim Nader
  • Aya Abdelnasser
  • Nada Megahed
  • Mohamed Basuony
  • Ahmed Shawky
  • Maryam Mahmoud
  • Reham Medhat
  • Abdelrahman S. Eldin
Original Article

Abstract

Hepatocellular carcinoma (HCC) is characterized by bad prognosis and is the second most common reason for cancer-linked mortality. Treatment with sorafenib (SRF) alone increases patient survival by only a few months. A causal link has been determined between angiotensin II (Ang-II) and HCC. However, the mechanisms underlying the tumorigenic effects of Ang-II remain to be elucidated. N-Nitrosodiethylamine was utilized to examine the effects of telmisartan (TEL) (15 mg/kg), SRF (30 mg/kg), and a combination of these two agents on HCC mice. Downregulation of NF-кBP65 mRNA expression and inhibition of the phosphorylation-induced activation of both ERK1/2 and NF-кB P65 were implicated in the anti-tumor effects of TEL and SRF. Consequent regression of malignant changes and improvements in liver function associated with reduced levels of AFP, TNF-α, and TGF-β1 were also confirmed. Anti-proliferative, anti-metastatic, and anti-angiogenic effects of treatment were indicated by reduced hepatic cyclin D1 mRNA expression, reduced MMP-2 levels, and reduced VEGF levels, respectively. TEL, but not SRF, demonstrated agonistic activity for PPARγ receptors, as evidenced by increased PPARγ DNA binding activity, upregulation of CD36, and HO-1 mRNA expression followed by increased liver antioxidant capacity. Both TEL and SRF inhibited TAK1 phosphorylation-induced activation, indicating that TAK1 might act as a central mediator in the interaction between ERK1/2 and NF-кB. TEL, by modulating the ERK1/2, TAK1, and NF-кB signaling axis in the context of PPARγ agonistic activity, exerted anti-tumor effects and increased tumor sensitivity to SRF. Therefore, TEL is an encouraging agent for further clinical trials regarding the management of HCC.

Keywords

Telmisartan N-Nitrosodiethylamine PPARγ ERK1/2 TAK1 NF-кB 

Abbreviations

CD36

Cluster of differentiation 36

ERK

Extracellular signal-regulated kinase

GST-P

Placental glutathione S-transferase

HO-1

Heme oxygenase 1

Iκ-Bα

Nuclear factor kappa-B inhibitor alpha

IKK

IkB kinase

MAPK

Mitogen-activated protein kinase

MEK

Mitogen-activated protein kinase

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

NFκB

Nuclear transcription factor kappa-B

PPARγ

Peroxisome proliferator-activated receptor gamma

TAK1

Transforming growth factor beta-activated kinase 1

Notes

Author’s contribution

SS conceived, designed, conducted the experiment, and analyzed data; AK, WS, and MS conceived, designed, and conducted the experiment; WA performed histological and immunohistochemical analysis; BE, KN, AA, NM, MB, AS, MM, RM, and AE conducted the experiment. All authors equally contributed in writing, reading, and approving the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Abdel-Ghany R, Rabia I, El-Ahwany E, Saber S, Gamal R, Nagy F, Mahmoud O, Hamad RS, Barakat W (2015) Blockade of PGE2, PGD2 receptors confers protection against prepatent schistosomiasis mansoni in mice. J Egypt Soc Parasitol 45:511–520PubMedGoogle Scholar
  2. Abdo W, Hirata A, Sakai H, El-Sawak A, Nikami H, Yanai T (2013) Combined effects of organochlorine pesticides heptachlor and hexachlorobenzene on the promotion stage of hepatocarcinogenesis in rats. Food Chem Toxicol 55:578–585PubMedGoogle Scholar
  3. Abdo W, Hirata A, Shukry M, Kamal T, Abdel-Sattar E, Mahrous E, Yanai T (2015) Calligonum comosum extract inhibits diethylnitrosamine-induced hepatocarcinogenesis in rats. Oncol Lett 10:716–722PubMedPubMedCentralGoogle Scholar
  4. Ali Z, Sudiro T, Mulia D (2015) Losartan effect on lowering TNF-[alpha] serum levels in asymptomatic hyperuricemia hypertension patients. J Hypertens 33:e33Google Scholar
  5. Anandanadesan R, Gong Q, Chipitsyna G, Witkiewicz A, Yeo CJ, Arafat HA (2008) Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling. J Gastrointest Surg 12:57–66PubMedGoogle Scholar
  6. Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) WHO classification of tumours of the digestive system. World Health OrganizationGoogle Scholar
  7. Brito AF, Abrantes AM, Tralhao JG, Botelho MF (2016) Targeting hepatocellular carcinoma: what did we discover so far? Oncol Rev 10:302PubMedPubMedCentralGoogle Scholar
  8. Christian JB, Lapane KL, Hume AL, Eaton CB, Weinstock MA, Trial V (2008) Association of ACE inhibitors and angiotensin receptor blockers with keratinocyte cancer prevention in the randomized VATTC trial. J Natl Cancer Inst 100:1223–1232PubMedGoogle Scholar
  9. Dai M, Al-Odaini AA, Fils-Aime N, Villatoro MA, Guo J, Arakelian A, Rabbani SA, Ali S, Lebrun JJ (2013) Cyclin D1 cooperates with p21 to regulate TGFbeta-mediated breast cancer cell migration and tumor local invasion. Breast Cancer Res 15:R49PubMedPubMedCentralGoogle Scholar
  10. De Paepe B, Verstraeten VM, De Potter CR, Bullock GR (2002) Increased angiotensin II type-2 receptor density in hyperplasia, DCIS and invasive carcinoma of the breast is paralleled with increased iNOS expression. Histochem Cell Biol 117:13–19PubMedGoogle Scholar
  11. Dhanasekaran R, Bandoh S, Roberts LR (2016) Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Res 5Google Scholar
  12. Fujita K, Yoneda M, Wada K, Mawatari H, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y, Maeyama S, Saito S (2007) Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. Dig Dis Sci 52:3455–3464PubMedGoogle Scholar
  13. Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J, Touraine J-L, Nakatani T, Yoshimura R (2008) Telmisartan is a potent target for prevention and treatment in human prostate cancer. Oncol Rep 20:295–300PubMedGoogle Scholar
  14. Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J, Touraine J-L, Nakatani T, Yoshimura R (2009) Telmisartan as a peroxisome proliferator-activated receptor-γ ligand is a new target in the treatment of human renal cell carcinoma. Mol Med Rep 2:193–198PubMedGoogle Scholar
  15. Guillemot L, Levy A, Raymondjean M, Rothhut B (2001) Angiotensin II-induced transcriptional activation of the cyclin D1 gene is mediated by Egr-1 in CHO-AT(1A) cells. J Biol Chem 276:39394–39403PubMedGoogle Scholar
  16. Herr D, Rodewald M, Fraser HM, Hack G, Konrad R, Kreienberg R, Wulff C (2008) Potential role of renin-angiotensin-system for tumor angiogenesis in receptor negative breast cancer. Gynecol Oncol 109:418–425PubMedGoogle Scholar
  17. Ishiguro H, Ishiguro Y, Kubota Y, Uemura H (2007) Regulation of prostate cancer cell growth and PSA expression by angiotensin II receptor blocker with peroxisome proliferator-activated receptor gamma ligand like action. Prostate 67:924–932PubMedGoogle Scholar
  18. Koyama N, Nishida Y, Ishii T, Yoshida T, Furukawa Y, Narahara H (2014) Telmisartan induces growth inhibition, DNA double-strand breaks and apoptosis in human endometrial cancer cells. PLoS One 9:e93050PubMedPubMedCentralGoogle Scholar
  19. Lee J-S, Chu I-S, Mikaelyan A, Calvisi DF, Heo J, Reddy JK, Thorgeirsson SS (2004) Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 36:1306–1311PubMedGoogle Scholar
  20. Lee LD, Mafura B, Lauscher JC, Seeliger H, Kreis ME, Gröne J (2014) Antiproliferative and apoptotic effects of telmisartan in human colon cancer cells. Oncol Lett 8:2681–2686PubMedPubMedCentralGoogle Scholar
  21. Lin SW, Lee MT, Ke FC, Lee PP, Huang CJ, Ip MM, Chen L, Hwang JJ (2000) TGFbeta1 stimulates the secretion of matrix metalloproteinase 2 (MMP2) and the invasive behavior in human ovarian cancer cells, which is suppressed by MMP inhibitor BB3103. Clin Exp Metastasis 18:493–499PubMedGoogle Scholar
  22. Liu H-q, Wei X-b, Sun R, Cai Y-w, Lou H-y, Wang J-W, Chen AF, Zhang X-M (2006) Angiotensin II stimulates intercellular adhesion molecule-1 via an AT 1 receptor/nuclear factor-κB pathway in brain microvascular endothelial cells. Life Sci 78:1293–1298PubMedGoogle Scholar
  23. Miyajima A, Kosaka T, Asano T, Asano T, Seta K, Kawai T, Hayakawa M (2002) Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. Cancer Res 62:4176–4179PubMedGoogle Scholar
  24. Ndisang JF (2014) Cross-talk between heme oxygenase and peroxisome proliferator-activated receptors in the regulation of physiological functions. Front Biosci (Landmark Ed) 19:916–935Google Scholar
  25. Ota K, Ito K, Suzuki T, Saito S, Tamura M, Hayashi S-i, Okamura K, Sasano H, Yaegashi N (2006) Peroxisome proliferator-activated receptor γ and growth inhibition by its ligands in uterine endometrial carcinoma. Clin Cancer Res 12:4200–4208PubMedGoogle Scholar
  26. Park GB, Ko HS, Kim D (2017) Sorafenib controls the epithelial-mesenchymal transition of ovarian cancer cells via EGF and the CD44-HA signaling pathway in a cell type-dependent manner. Mol Med Rep 16:1826–1836PubMedPubMedCentralGoogle Scholar
  27. Ranjan A, Iyer SV, Ward C, Link T, Diaz FJ, Dhar A, Tawfik OW, Weinman SA, Azuma Y, Izumi T (2018) MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma. Oncotarget 9:21429PubMedPubMedCentralGoogle Scholar
  28. Remels A, Langen R, Gosker HR, Russell A, Spaapen F, Voncken J, Schrauwen P, Schols AM (2009) PPARγ inhibits NF-κB-dependent transcriptional activation in skeletal muscle. A J Physiol Endocrinol Metab 297:E174–E183Google Scholar
  29. Rosenthal T, Gavras I (2009) Angiotensin inhibition and malignancies: a review. J Hum Hypertens 23:623–635PubMedGoogle Scholar
  30. Saber S (2018) Angiotensin II: a key mediator in the development of liver fibrosis and cancer. Bull Nat Res Centre 42:18Google Scholar
  31. Saber S, Goda R, El-Tanbouly GS, Ezzat D (2018a) Lisinopril inhibits nuclear transcription factor kappa B and augments sensitivity to silymarin in experimental liver fibrosis. Int Immunopharmacol 64:340–349PubMedGoogle Scholar
  32. Saber S, Khalil RM, Abdo WS, Nassif D, El-Ahwany E (2019) Olmesartan ameliorates chemically-induced ulcerative colitis in rats via modulating NFκB and Nrf-2/HO-1 signaling crosstalk. Toxicol Appl Pharmacol 364:120–132PubMedGoogle Scholar
  33. Saber S, Mahmoud A, Helal N, El-Ahwany E, Abdelghany R (2018b) Liver protective effects of renin-angiotensin system inhibition have no survival benefits in hepatocellular carcinoma induced by repetitive administration of diethylnitrosamine in mice. Open Access Maced J Med Sci 6:955–1179PubMedPubMedCentralGoogle Scholar
  34. Saber S, Mahmoud AA, Helal NS, El-Ahwany E, Abdelghany RH (2017) Losartan, an angiotensin-II type 1 receptor blocker, attenuates CCl4-induced liver fibrosis with a positive impact on survival in mice. World J Pharm Pharm Sci 5:121–126Google Scholar
  35. Saber S, Mahmoud AAA, Goda R, Helal NS, El-ahwany E, Abdelghany RH (2018c) Perindopril, fosinopril and losartan inhibited the progression of diethylnitrosamine-induced hepatocellular carcinoma in mice via the inactivation of nuclear transcription factor kappa-B. Toxicol Lett 295:32–40PubMedGoogle Scholar
  36. Saber S, Mahmoud AAA, Helal NS, El-Ahwany E, Abdelghany RH (2018d) Renin–angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B. Can J Physiol Pharmacol 96:569–576PubMedGoogle Scholar
  37. Sabio G, Davis RJ (2014) TNF and MAP kinase signalling pathways. Seminars in immunology. Elsevier, pp 237–245Google Scholar
  38. Schoenleber SJ, Kurtz DM, Talwalkar JA, Roberts LR, Gores GJ (2009) Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer 100:1385–1392PubMedPubMedCentralGoogle Scholar
  39. Sharma V, McNeill JH (2009) To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol 157:907–921PubMedPubMedCentralGoogle Scholar
  40. Shirakami Y, Gottesman ME, Blaner WS (2012) Diethylnitrosamine-induced hepatocarcinogenesis is suppressed in lecithin:retinol acyltransferase-deficient mice primarily through retinoid actions immediately after carcinogen administration. Carcinogenesis 33:268–274PubMedGoogle Scholar
  41. Shlomai A, de Jong YP, Rice CM (2014) Virus associated malignancies: the role of viral hepatitis in hepatocellular carcinoma. Semin Cancer Biol 26:78–88PubMedGoogle Scholar
  42. Sjoberg T, Garcia Rodriguez LA, Lindblad M (2007) Angiotensin-converting enzyme inhibitors and risk of esophageal and gastric cancer: a nested case-control study. Clin Gastroenterol Hepatol 5:1160–1166 e1161PubMedGoogle Scholar
  43. Song Y, Jin SJ, Cui LH, Ji XJ, Yang FG (2013) Immunomodulatory effect of Stichopus japonicus acid mucopolysaccharide on experimental hepatocellular carcinoma in rats. Molecules 18:7179–7193PubMedPubMedCentralGoogle Scholar
  44. Stangier J, Su C, Roth W (2000) Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res 28:149–167PubMedGoogle Scholar
  45. Sullivan DE, Ferris M, Pociask D, Brody AR (2005) Tumor necrosis factor-α induces transforming growth factor-β1 expression in lung fibroblasts through the extracellular signal–regulated kinase pathway. Am J Respir Cell Mol Biol 32:342–349PubMedGoogle Scholar
  46. Takahashi T, Ueno H, Shibuya M (1999) VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18:2221–2230PubMedGoogle Scholar
  47. Turkseven S, Kruger A, Mingone CJ, Kaminski P, Inaba M, Rodella LF, Ikehara S, Wolin MS, Abraham NG (2005) Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes. Am J Phys Heart Circ Phys 289:H701–H707Google Scholar
  48. Wei Y, Sowers JR, Clark SE, Li W, Ferrario CM, Stump CS (2008) Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-κB activation via NADPH oxidase. Am J Physiol Endocrinol Metab 294:E345–E351PubMedGoogle Scholar
  49. Wu M, Peng Z, Zu C, Ma J, Lu S, Zhong J, Zhang S (2016) Losartan attenuates myocardial endothelial-to-mesenchymal transition in spontaneous hypertensive rats via inhibiting TGF-beta/Smad signaling. PLoS One 11:e0155730PubMedPubMedCentralGoogle Scholar
  50. Yang D, Ma S, Li D, Tang B, Yang Y (2009) Angiotensin II receptor blockade improves matrix metalloproteinases/tissue inhibitor of matrix metalloproteinase-1 balance and restores fibronectin expression in rat infarcted myocardium. Biochem Biophys Res Commun 388:606–611PubMedGoogle Scholar
  51. Zheng X, Gai X, Han S, Moser CD, Hu C, Shire AM, Floyd RA, Roberts LR (2013) The human sulfatase 2 inhibitor 2,4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and hedgehog/GLI1 signaling. Genes Chromosom Cancer 52:225–236PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sameh Saber
    • 1
    Email author
  • Ahmed E. Khodir
    • 1
  • Wafaa E. Soliman
    • 2
    • 3
  • Mohamed M. Salama
    • 4
  • Walied S. Abdo
    • 5
  • Baraah Elsaeed
    • 4
  • Karim Nader
    • 4
  • Aya Abdelnasser
    • 4
  • Nada Megahed
    • 4
  • Mohamed Basuony
    • 4
  • Ahmed Shawky
    • 4
  • Maryam Mahmoud
    • 4
  • Reham Medhat
    • 4
  • Abdelrahman S. Eldin
    • 4
  1. 1.Department of Pharmacology, Faculty of PharmacyDelta University for Science and TechnologyGamasa CityEgypt
  2. 2.Department of Microbiology and Biotechnology, Faculty of PharmacyDelta University for Science and TechnologyGamasaEgypt
  3. 3.Department of Biomedical Science, Faculty of Clinical PharmacyKing Faisal UniversityAl-AhsaSaudi Arabia
  4. 4.Department of Biochemistry, Faculty of PharmacyDelta University for Science and TechnologyGamasaEgypt
  5. 5.Department of Pathology, Faculty of Veterinary MedicineKafrelsheikh UniversityKafrelsheikhEgypt

Personalised recommendations