Medicinal Chemistry Research

, Volume 26, Issue 7, pp 1567–1573 | Cite as

Mechanistic investigation of hepato-protective potential for cucurbitacins

  • Hajer M. Arjaibi
  • Mahmoud S. Ahmed
  • Fathi T. Halaweish
Original Research


Hepatocellular carcinoma is a major example for inflammatory-associated cancer. cucurbitacins are natural triterpenoids known for their potent anticancer and anti-inflammatory activities. Recent studies showed that cucurbitacins protect the HepG2 cell lines against carbon tetrachloride-induced toxicity, however the mechanism is unknown. A molecular docking study coupled with in vitro biological assays were conducted to test the hepatoprotective effect of cucurbitacin on the inhibition of potential inflammatory factors. The effect of cucurbitacins on the activation of NF-kB pathway was analyzed using in cell-based NF-kB immunoassay. Enzyme-linked immunosorbent assays revealed the potential of Cuc D and dihydro cucurbitacin D to prevent the production of tumor necrosis factor-alpha and interleukin-6 from HSC-T6 cells. Thus, Cuc D and dihydro cucurbitacin D could have hepatoprotective effects on the activated rat HSC-T6 cells due to inhibition of the production of tumor necrosis factor-alpha and interleukin-6 through NF-kB pathway. In-silico molecular modeling data revealed potential cucurbitacin analogs with higher binding affinity to the hydrophobic pocket of NF-kB and IKKβ compared to standard IKK inhibitor (PS-1145).


Cucurbitacins Hepatoprotection HSC-T6 NF-kB TNF-α 



The authors would like to thank the Libyan ministry of higher education for funding this work, OpenEye® molecular modeling software for supporting an academic license, and Dr. Friedman (Mount. Sinai Hospital, NY) for providing the HSC-T6 cell lines. This work was supported by the Libyan ministry of higher education.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Adewusi E, Afolayan A (2010) Review of natural products with Hepatoprotective activity. J Med Plants Res 4:1318–1334Google Scholar
  2. Ahmed MS, El-Senduny F, Taylor J, Halaweish F (2017) Biological screening of cucurbitacin inspired estrone analogs targeting mitogen activated protein kinase (MAPK) pathway. Chem Biol Drug Des, doi: 10.1111/cbdd.12963. [Epub ahead of print]
  3. Ahmed MS, Halaweish FT (2014) Cucurbitacins: potential candidates targeting mitogen-activated protein kinase pathway for treatment of melanoma. J Enzyme Inhib Med Chem 29:162–167CrossRefPubMedGoogle Scholar
  4. Ahmed MS, Kopel L, Halaweish F (2014) Structural optimization and biological screening of a steroidal scaffold possessing cucurbitacin-like functionalities as B-raf inhibitors. ChemMedChem 9:1361–1367CrossRefPubMedGoogle Scholar
  5. Alghasham A (2013) Cucurbitacins - a promising target for cancer therapy. Int J Med Health Sci 7:77–89Google Scholar
  6. Bartalis J, Halaweish F (2011) In vitro and QSAR studies of cucurbitacins on HepG2 and HSC-T6 liver cell lines. Bioorg Med Chem 19:2757–2766CrossRefPubMedGoogle Scholar
  7. Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA (2009) Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci 1155:206–221CrossRefPubMedGoogle Scholar
  8. Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX (2005) Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep 22:386–399CrossRefPubMedGoogle Scholar
  9. Covert M, Leung H, Gaston E, Baltimore D (2005) Achieving stability of lipopolysaccharide-induced NF-kB activation. Science 309:1854–1857CrossRefPubMedGoogle Scholar
  10. Dhiman K, Gupta A, Sharma D, Gill N, Goyal A (2012) A review on the medicinally important plants of the family cucurbitaceae. Asian J Clin Nutr 4:16–26CrossRefGoogle Scholar
  11. Escandell J, Recio M, Máñez S, Giner R, Cerdá-Nicolás M, Ríos J (2007) Cucurbitacin R reduces the inflammation and bone damage associated with adjuvant arthritis in lewis rats by suppression of tumor necrosis factor-alpha in T lymphocytes and macrophages. J Pharmacol Exp Ther 320:581–590CrossRefPubMedGoogle Scholar
  12. Hawkins PCD, Skillman AG, Warren GL, Ellingson BA, Stahl MT (2010) Conformer generation with OMEGA: algorithm and validation using high quality structures from the protein databank and cambridge structural database. J Chem Inf Model 50:572–584CrossRefPubMedPubMedCentralGoogle Scholar
  13. Jayaprakasam B, Seeram NP, Nair MG (2003) Anticancer and antiinflammatory activities of cucurbitacins from cucurbita andreana. Cancer lett 189:11–16CrossRefPubMedGoogle Scholar
  14. Jia Q, Cheng W, Yue Y, Hu Y, Zhang J, Pan X, Xu Z, Zhang P (2015) Cucurbitacin E inhibits TNF-α-induced inflammatory cytokine production in human synoviocyte MH7A cells via suppression of PI3K/Akt/NF-κB pathways. Int Immunopharmacol 29:884–890CrossRefPubMedGoogle Scholar
  15. Jin R, Jin X, Dat N, Lee J (2011) Cucurbitacin B suppresses the transactivation activity of RelA/p65. J Cell Biochem 112:1643–1650CrossRefPubMedGoogle Scholar
  16. Karin M, Delhase M (2000) The IKB kinase (IKK) and NF-kB : key elements of proinflammatory signalling. Semin Immunol 12:85–98CrossRefPubMedGoogle Scholar
  17. Maeda S, Kamata H, Luo JL, Leffert H, Karin M (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–990CrossRefPubMedGoogle Scholar
  18. Mcgann M (2011) FRED pose prediction and virtual screening accuracy. J Chem Inf Model 5:578–596CrossRefGoogle Scholar
  19. Mühlbauer M, Weiss T, Thasler W, Gelbmann W, Schnabl B, Schölmerich J, Hellerbrand C (2004) LPS-mediated NFkappaB activation varies between activated human hepatic stellate cells from different donors. Biochem Biophys Res Commun 325:191–197CrossRefPubMedGoogle Scholar
  20. Nakagawa H, Maeda S, Yoshida H, Tateishi R, Masuzaki R, Ohki T, Hayakawa Y, Kinoshita H, Yamakado M, Kato N, Shiina S, Omata M (2009) Serum IL-6 Levels and the risk for hepatocarcinogenesis in chronic hepatitis c patients: an analysis based on gender differences. Int J Cancer 125:2264–2269CrossRefPubMedGoogle Scholar
  21. Park C, Lim H, Han K, Baek S, Sohn O, Lee W, Kim Y, Yun H, Baek K (2004) Inhibition of nitric oxide generation by 23, 24- dihydrocucurbitacin D in mouse peritoneal macrophages. J Pharmacol Exp Ther 309:705–710CrossRefPubMedGoogle Scholar
  22. Popa C, Netea MG, van Riel PL, van der Meer JW, Stalenhoef AF (2007) The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res 48:751–762CrossRefPubMedGoogle Scholar
  23. Rosenfeld M, Prichard L, Shiojiri N, Fausto N (2000) Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice. Am J Pathol 156:997–1007CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2017

Authors and Affiliations

  • Hajer M. Arjaibi
    • 1
  • Mahmoud S. Ahmed
    • 2
  • Fathi T. Halaweish
    • 1
  1. 1.Department of Chemistry & BiochemistrySouth Dakota State UniversityBrookingsUSA
  2. 2.Department of Pharmaceutical Chemistry, Faculty of PharmacyThe British University in EgyptAl-Sherouk CityEgypt

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