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


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.


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



Cluster of differentiation 36


Extracellular signal-regulated kinase


Placental glutathione S-transferase


Heme oxygenase 1


Nuclear factor kappa-B inhibitor alpha


IkB kinase


Mitogen-activated protein kinase


Mitogen-activated protein kinase


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


Nuclear transcription factor kappa-B


Peroxisome proliferator-activated receptor gamma


Transforming growth factor beta-activated kinase 1


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.


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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

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