INSILICO ANALYSIS OF DIETARY AGENTS AS ANTICANCER INHIBITORS OF INSULIN LIKE GROWTH FACTOR 1 RECEPTOR (IGF1R)

  • Nupur Soni Dept. of Bioinformatics, 2Dept. of Mathematics, Maulana Azad National Institute of Technology, Bhopal, India
  • K. R Pardasani Maulana Azad National Institute of Technology
  • Somdutt Mujwar Maulana Azad National Institute of Technology

Abstract

Objective: Insulin-like growth factor 1 receptor (IGF-1R) is over-expressed in a number of cancer cell lines and has been implicated to play a role in oncogenesis and suppression of apoptosis. Thus, the inhibition of IGF-1R activity leads to tumor regression and renders IGF-1R a plausible target for the development of anti-cancer drugs. Dietary agents are known to interfere with IGF signaling and offer a foundation for developing nontoxic agents that override any toxicity associated with synthetic IGF inhibitors. This study is designed to obtain structural motifs and active residues that preferentially interact with IGF1Rand to identify the phytochemicals from different plants and act as potential anticancer drug leads

Methods: Thus, six dietary agents known to interfere directly with circulating levels of IGF1R were undertaken for docking studies. A molecular docking simulation model of IGF1R with its bound ligand was established and validated to be used as a reference model for the study.

Results: The active site residuesGLU1080, MET 1082, GLU1081, GLU1027, GLU1145 and ARG1003 were found to play a significant role in binding mechanism. The ADME properties and drug likeliness of the ligands were rigorously analyzed under four criteria of known successful drug activity in the areas of GPCR ligand activity, ion channel modulation, kinase inhibition activity, nuclear receptor ligand activity and enzyme inhibition. The dietary agents Apigenin and Luteolin demonstrated reliable interaction with IGF1R (-5.78Kcal/mol and-5.70 Kcal/mol respectively)and displayed good pharmacokinetics properties.

Conclusion: It is concluded that the explored dietary agents offer profound promise to be used natural inhibitors of IGF1R and thus may be useful for the preparation of different combinations and formulations for the management of tumors.

 

Keywords: IGF-1R Inhibitors, Dietary agents, Insilico modeling, Binding affinities, Molecular Docking

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References

1. Hubbard SR. Crystal structure of the activated insulin receptor kinase in complex with peptide substrate and ATP analog. Embo J 1999;716:5572-81.
2. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer 2003;107:873–7.
3. LeRoith D, Helman L. The new kid on the block(ade) of the IGF-I receptor. Cancer Cell 2004:5:201–2.
4. Moschos SJ, Mantzoros CS. The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Onco 2002;63:317–32.
5. Warshamana-Greene GS, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal GW. The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 2005;11:1563–71.
6. Mountzios G, Kostopoulos I, Kotoula V, Sfakianaki I, Fountzilas E, Markou K, et al. Insulin-like growth factor 1 receptor (IGF1R) expression and survival in operable squamous-cell laryngeal cancer. PLoS One 2013;8:e54048. doi: 10.1371/journal.pone.0054048. [Epub 2013 Jan 24]
7. SellC, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth receptor. Proc Natl Acad Sci USA 1993;90:112-7.
8. Carboni JM, Lee AV, Hadsell DL, Rowley BR, Lee FY, Bol DK. Tumor development bytransgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res 2005;65:3781–90.
9. Lopez T, Hanahan D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 2002;1:339–53.
10. Yakar S, Leroith D, Brodt P. The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: lessons from animal models. Cytokine Growth Factor Rev 2005;16:407–20.
11. Haluska P, Shaw H, Batzel GN, Molife LR, Adjei AA, Yap TA. Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors. ASCO Meeting Abstracts. ASCO Meeting Abstracts 2007;25:3586.
12. Chowdhury S, Dominguez I, Sharratt E, Spernyak J, Brattain MG, Ashwani R. Anti-tumor activity of the IGF-1R kinase inhibitor PQIP in colon cancer. Clin Exp Pharmacol June 2013;S4:5.
13. Fang J, Zhou Q, Shi X, Jiang B. Luteolin inhibits insulin-like growth factor 1receptor signaling in prostate cancer cells Carcinogenesis. Adv Carcinog 2007;28:713-23.
14. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discovery 2005;4:206-20.
15. Rollinger JM, Stuppner H, Langer T. Virtual screening for the discovery of bioactive natural products. Prog Drug Res 2008;65:213-49.
16. Adhami VM, Afaq F. Insulin-like growth factor-i axis as a pathway for cancer chemoprevention. Clin Can Res 200612:5611.
17. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. Multiple biological activities of curcumin: a short review. Life Sci 2006;78:2081-7.
18. Hwang YW, Kim SY, Jee SH, Kim YN, Nam CM. Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutr Cancer 2009;61:598-606.
19. Han RM, Tian YX, Liu Y, Chen CH, Ai XC, Zhang JP, et al. Comparison of flavonoids and isoflavonoids as antioxidants. J Agric Food Chem 2009;57:3780-5.
20. Si H, Liu D. Phytochemical genistein in the regulation of vascular function: new insights. Curr Med Chem Curr Med Chem 2007;14:2581–9.
21. Kim HP, Mani I, Iversen L, Ziboh VA. Effects of naturally-occurring flavonoids and bioflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pig. Prostaglandins Leukotrienes Essent Fatty Acids 1998;58:17-24.
22. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 1995;87:1767–76.
23. Basu A, Imrhan V. Tomatoes versus lycopene in oxidative stress and carcinogenesis: conclusions from clinical trials. Eur J Clin Nut Vol 2007;61:295–303.
24. Stahl W, Sies H. Lycopene: a biologically important carotenoid for humans? Arch Biochem Biophys 1996;1:1-9.
25. Tyagi A, Bhatia N, Condon MS, Bosland MC, Agarwal C. Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells. Prostate 2002;53:211–7.
26. Ligeret H, Brault A, Vallerand D, Haddad Y, Haddad PS. Antioxidant and mitochondrial protective effects of silibinin in cold preservation–warm reperfusion liver injury. J Ethnopharmacol 2008;115:507-14.
27. Agarwal R, Mallikarjuna GU, Dhanalakshmi S, Mohan S, Singh RP. Silibinin inhibits ultraviolet B radiation-induced mitogenic and survival signaling, and associated proliferation and apoptosis in SKH-1 mouse skin: implications for the prevention of photocarcinogenesis. Proc Am Assoc Cancer Res 2005;46:457-65.
28. Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets 2008;8:634-46.
29. Leung HW, Kuo CL, Yang WH, Lin CH, Lee HZ. Antioxidant enzymes activity involvement in luteolin-induced human lung squamous carcinoma CH27 cell apoptosis. Eur J Pharm 2006;534:12–8.
30. http://autodock.scripps.edu. [Last accessed on 20 Apr 2015].
31. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605-12.
32. http://www.molinspiration.com. [Last accessed on 20 Apr 2015].
33. http://biochem.ucl.ac.uk/bsm/ligplot/ligplot.html. [Last accessed on 20 Apr 2015].
34. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 1997;23:1-25.
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How to Cite
Soni, N., K. R. Pardasani, and S. Mujwar. “INSILICO ANALYSIS OF DIETARY AGENTS AS ANTICANCER INHIBITORS OF INSULIN LIKE GROWTH FACTOR 1 RECEPTOR (IGF1R)”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 7, no. 9, July 2015, pp. 191-6, https://innovareacademics.in/journals/index.php/ijpps/article/view/4954.
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