Skip to main content
SpringerLink
Log in

Antioxidant potential of ganoderic acid in Notch-1 protein in neuroblastoma

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Neuroblastoma is a childhood tumor arising from developing a sympathetic nervous system and causes around 10% of pediatric tumors. Despite advancement in the use of sophisticated techniques in molecular biology, neuroblastoma patient’s survivability rate is very less. Notch pathway is significant in upholding cell maintenance and developmental process of organs. Notch-1 proteins are a ligand-activated transmembrane receptor which decides the fate of the cell. Notch signaling leads to transcription of genes which indulged in numerous diseases including tumor progression. Ganoderic acid, a lanosterol triterpene, isolated from fungus Ganoderma lucidum with a wide range of medicinal values. In the present study, various isoforms of the ganoderic acid and natural inhibitors were docked by molecular docking using Maestro 9 in the Notch-1 signaling pathway. The receptor-based molecular docking exposed the best binding interaction of Notch-1 with ganoderic acid A with GScore (− 8.088), kcal/mol, Lipophilic EvdW (− 1.74), Electro (− 1.18), Glide emodel (− 89.944) with the active participation of Arg 189, Arg 199, Glu 232 residues. On the other hand natural inhibitor, curcumin has GScore (− 7.644), kcal/mol, Lipophilic EvdW (− 2.19), Electro (− 0.73), Glide emodel (− 70.957) with Arg 75 residues involved in docking. The ligand binding affinity of ganoderic acid A in Notch-1 is calculated using MM-GBSA (− 76.782), whereas curcumin has (− 72.815) kcal/mol. The QikProp analyzed the various drug-likeness parameters such as absorption, distribution, metabolism, excretion, and toxicity (ADME/T) and isoforms of ganoderic acid require some modification to fall under Lipinski rule. The ganoderic acid A and curcumin were the best-docked among different compounds and exhibits downregulation in Notch-1 mRNA expression and inhibits proliferation, viability, and ROS activity in IMR-32 cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

ROS:

Reactive oxygen species

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

References

  1. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66(4):649–661

    Article  CAS  PubMed  Google Scholar 

  2. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776

    Article  CAS  PubMed  Google Scholar 

  3. Ma B, Simala-Grant JL, Taylor DE (2006) Fucosylation in prokaryotes and eukaryotes. Glycobiology 16(12):158R–184R

    Article  CAS  PubMed  Google Scholar 

  4. Oswald F, Täuber B, Dobner T, Bourteele S, Kostezka U, Adler G, Liptay S, Schmid RM (2001) p300 acts as a transcriptional coactivator for mammalian Notch-1. Mol Cell Biol 21(22):7761–7774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sjölund J, Manetopoulos C, Stockhausen M-T, Axelson H (2005) The Notch pathway in cancer: differentiation gone awry. Eur J Cancer 41(17):2620–2629

    Article  CAS  PubMed  Google Scholar 

  6. Gill B, Alex J, Kumar S (2016) Missing link between microRNA and prostate cancer. Tumour Biol J Int Soc Oncodev Biol Med 37(5):5683–5704

    Article  CAS  Google Scholar 

  7. Grabher C, von Boehmer H, Look AT (2006) Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 6(5):347–359

    Article  CAS  PubMed  Google Scholar 

  8. Jang M-S, Zlobin A, Kast WM, Miele L (2000) Notch signaling as a target in multimodality cancer therapy. Curr Opin Mol Ther 2(1):55–65

    CAS  PubMed  Google Scholar 

  9. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, Hui C-C, Clevers H, Dotto GP, Radtke F (2003) Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33(3):416–421

    Article  CAS  PubMed  Google Scholar 

  10. Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Nara N, Tohda S (2009) Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res 29(11):4629–4632

    CAS  PubMed  Google Scholar 

  11. Li L, Zhang X, Cui L, Wang L, Liu H, Ji H, Du Y (2013) Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res 1497:32–39

    Article  CAS  PubMed  Google Scholar 

  12. Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH (2006) Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 106(11):2503–2513

    Article  CAS  PubMed  Google Scholar 

  13. Wang X, Wu Q, Yang X, Zhang L, Wu Y, Lu C (2010) Effects of celastrol on grouwth inhibition of U937 leukemia cells through the regulation of the Notchl/NF-KB signaling pathway in vitrol. Chin J Cancer 29(4):385

    Article  PubMed  Google Scholar 

  14. Gill BS, Sharma P, Kumar R, Kumar S (2016) Misconstrued versatility of Ganoderma lucidum: a key player in multi-targeted cellular signaling. Tumor Biol 37(3):2789–2804

    Article  CAS  Google Scholar 

  15. Gill BS, Navgeet G, Kumar S (2017) Ganoderma lucidum targeting lung cancer signaling: a review. Tumor Biol 39(6):1010428317707437

    Article  Google Scholar 

  16. Gill BS, Sharma P, Kumar S (2016) Chemical composition and antiproliferative, antioxidant, and proapoptotic effects of fruiting body extracts of the Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (Agaricomycetes), from India. Int J Med Mushrooms 18(7):599–607

    Article  Google Scholar 

  17. Gill BS, Kumar S (2016) Triterpenes in cancer: significance and their influence. Mol Biol Rep 43(9):881–896

    Article  CAS  PubMed  Google Scholar 

  18. Gill BS, Kumar S (2015) Differential algorithms-assisted molecular modeling-based identification of mechanistic binding of ganoderic acids. Med Chem Res 24(9):3483–3493

    Article  CAS  Google Scholar 

  19. Gill BS, Kumar S (2016) Ganoderic acid targeting multiple receptors in cancer: in silico and in vitro study. Tumor Biol 37:1–20

    Google Scholar 

  20. Gill BS, Kumar S (2018) Ganoderic acid A targeting β-catenin in Wnt signaling pathway: in silico and in vitro study. Interdiscip Sci Comput Life Sci 10(2):233–243

    Article  CAS  Google Scholar 

  21. Ehebauer MT, Chirgadze DY, Hayward P, Martinez Arias A, Blundell TL (2005) High-resolution crystal structure of the human Notch 1 ankyrin domain. Biochem J 392(Pt 1):13–20. https://doi.org/10.1042/bj20050515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gill BS, Kumar S (2016) Evaluating anti-oxidant potential of ganoderic acid A in STAT 3 pathway in prostate cancer. Mol Biol Rep 43(12):1411–1422

    Article  CAS  PubMed  Google Scholar 

  23. Yao P, Nussler A, Liu L, Hao L, Song F, Schirmeier A, Nussler N (2007) Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol 47(2):253–261

    Article  CAS  PubMed  Google Scholar 

  24. Farombi EO, Shrotriya S, Na H-K, Kim S-H, Surh Y-J (2008) Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food Chem Toxicol 46(4):1279–1287

    Article  CAS  PubMed  Google Scholar 

  25. Seo WY, Goh AR, Ju SM, Song HY, Kwon D-J, Jun J-G, Kim BC, Choi SY, Park J (2011) Celastrol induces expression of heme oxygenase-1 through ROS/Nrf2/ARE signaling in the HaCaT cells. Biochem Biophys Res Commun 407(3):535–540

    Article  CAS  PubMed  Google Scholar 

  26. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118(45):11225–11236

    Article  CAS  Google Scholar 

  27. Repasky MP, Shelley M, Friesner RA (2007) Flexible ligand docking with Glide. Curr Protoc Bioinform 8(1):8–12

    Google Scholar 

  28. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47(7):1739–1749

    Article  CAS  Google Scholar 

  29. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49(21):6177–6196

    Article  CAS  Google Scholar 

  30. Sitkoff D, Sharp KA, Honig B (1994) Accurate calculation of hydration free energies using macroscopic solvent models. J Phys Chem 98(7):1978–1988

    Article  CAS  Google Scholar 

  31. Lyne PD, Lamb ML, Saeh JC (2006) Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J Med Chem 49(16):4805–4808

    Article  CAS  Google Scholar 

  32. Jorgensen WL, Duffy EM (2002) Prediction of drug solubility from structure. Adv Drug Deliv Rev 54(3):355–366

    Article  CAS  PubMed  Google Scholar 

  33. Gill BS, Kumar S (2017) Ganoderic acid modulating TNF and its receptors: in silico and in vitro study. Med Chem Res 26(6):1336–1348

    Article  CAS  Google Scholar 

  34. Gill BS, Kumar S, Navgeet (2017) Ganoderic acid targeting nuclear factor erythroid 2—related factor 2 in lung cancer. Tumor Biol 39(3):1010428317695530

    Article  Google Scholar 

  35. Anand SS, Gill BS (2015) Breakthroughs in epigenetics. PharmaTutor 3(7):16–24

    CAS  Google Scholar 

  36. Fatmawati S, Shimizu K, Kondo R (2011) Ganoderol B: a potent α-glucosidase inhibitor isolated from the fruiting body of Ganoderma lucidum. Phytomedicine 18(12):1053–1055

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Central University of Punjab, Bathinda, for providing the necessary facilities to carry out the present work.

Author information

Author notes

  1. Balraj Singh Gill and Navgeet contributed equally to the work.

Authors and Affiliations

  1. Centre for Biosciences, Central University of Punjab, Bathinda, 151001, India

    Balraj Singh Gill

  2. Department of Higher Education, Shimla, Himachal Pradesh, India

    Balraj Singh Gill

  3. Department of Biotechnology, KMV College, Jalandhar, Punjab, India

    Navgeet

  4. Centre for Plant Sciences, Central University of Punjab, Bathinda, 151001, India

    Sanjeev Kumar

Authors
  1. Balraj Singh Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Navgeet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sanjeev Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Balraj Singh Gill or Sanjeev Kumar.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gill, B.S., Navgeet & Kumar, S. Antioxidant potential of ganoderic acid in Notch-1 protein in neuroblastoma. Mol Cell Biochem 456, 1–14 (2019). https://doi.org/10.1007/s11010-018-3485-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3485-7

Keywords

Search

Navigation