ANTIPROLIFERATIVE ACTIVITY OF N-BUTANOL FLORAL EXTRACT FROM BUTEA MONOSPERMA AGAINST HCT 116 COLON CANCER CELLS; DRUG LIKENESS PROPERTIES AND IN SILICO EVALUATION OF THEIR ACTIVE COMPOUNDS TOWARD GLYCOGEN SYNTHASE KINASE-3Î²/AXIN AND Î²-CATENIN/T-CELL FACTO
Objective: The aim was to study the inhibitory effect of n-butanol fraction of Butea monosperma floral extracts (NBF-BMFE) against HCT116 cells.
Moreover, the drug-likeness properties and in silico evaluation of their active compounds toward glycogen synthase kinase-3Î² (GSK-3Î²)/Axin and
Î²-catenin/T-Cell factor-4 (Tcf-4) complex proteins.
Methods: The three-dimensional protein structures were incurred from RCSB protein data bank, and their active site amino acids predicted using
CASTp server. Similarly, the NBE-BMFE phytochemicals were retrieved from PubChem Database then their absorption, distribution, metabolism,
excretion, and toxicity (ADMET)-related descriptors were calculated by using the admetSAR along with ACD/i-lab software. The docking analysis
was performed by using AutoDock 4.2. Concurrently, the NBF-BMFE were experimentally characterized by using liquid chromatography/mass
spectrometry (LC/MS) besides their anticancer activity was assessed against HCT-116 human colon cancer cells.
Results: The docking studies results showed that the NBF-BMFE phytochemicals showed good hydrogen bond interaction against GSK-3Î²/Axin
(4B7T) and Î²-catenin/Tcf-4 (1JPW) complex proteins. Moreover, the in silico results of ADMET factors were also satisfying correspondingly. The
LC/MS results revealed that the NBF-BMFE contains isocoreopsin, butrin and isobutrin as major compounds, and it has significant anticancer activity
(Ëƒ100 Î¼M) against HCT-116 human colon cancer cells.
Conclusion: Overall our results concluded that all the NBF-BMFE had significant inhibitory effect on HCT-116 cells plus good binding interaction
with 4B7T and 1JPW, in specific isocoreopsin, butein and butin showed promising agents to develop as potent drug molecules against colorectal
Keywords: Colorectal cancer, Butea monosperma, Absorption; distribution; metabolism; excretion and toxicity, Molecular docking, Glycogen synthase
kinase-3Î²/Axin, Î²-catenin/T-Cell factor-4.
2. Wang W, Liu H, Wang S, Hao X, Li L. A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/ÃŸ-catenin signaling and colon cancer cell tumorigenesis. Cell Res 2011;21(5):730-40.
3. Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 2003;5(3):367-77.
4. Cadigan KM, Nusse R. Wnt signaling: A common theme in animal development. Genes Dev 1997;11(24):3286-305.
5. Clevers H, Nusse R. Wnt/ÃŸ-catenin signaling and disease. Cell 2012;149(6):1192-205.
6. Yavropoulou MP, Yovos JG. The role of the Wnt signaling pathway in osteoblast commitment and differentiation. Hormones (Athens) 2007;6(4):279-94.
7. Luu HH, Zhang R, Haydon RC, Rayburn E, Kang Q, Si W, et al. Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets 2004;4(8):653-71.
8. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87(2):159-70.
9. Sehrawat A, Khan TH, Prasad L, Sultana S. Butea monosperma and chemomodulation: Protective role against thioacetamide-mediated hepatic alterations in Wistar rats. Phytomedicine 2006;13(3):157-63.
10. Zafar R, Nahid A, Abubakar K, Khursheed AK, Tariq MH. Butrin, isobutrin, and butein from medicinal plant Butea monosperma selectively inhibit nuclear factor-ÐšB in activated human mast cells: Suppression of tumor necrosis factor-Î±, interleukin (IL)-6, and IL-8. J Pharmacol Exp Ther 2010;333(2):354-63.
11. Mathan G, Fatima G, Saxena AK, Chandan BK, Jaggi BS, Gupta BD, et al. Chemoprevention with aqueous extract of Butea monosperma flowers results in normalization of nuclear morphometry and inhibition of a proliferation marker in liver tumors. Phytother Res 2011;25(3):324-8.
12. Navaneethakrishnan P, Prashantha CN, Boopathi S, Sabitha R, Mathan G. In silico design of Butea monosperma floral derived compounds and its inhibitory effect on Î²-catenin, GSK-3Î² and APC complex proteins in colorectal cancer. Int J Drug Discov 2013;5(1):191-7.
13. Wagner H, Geyer B, Fiebig M, Kiso Y, Hikino H. Isobutrin and butrin, the antihepatotoxic principles of Butea monosperma flowers. Planta Med 1986;77-9.
14. Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, et al. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Mol Cell Biol 2001;21(15):5132â€‘41.
15. Jian H, Shen X, Liu I, Semenov M, He X, Wang XF. Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 2006;20(6):666-74.
16. Liu W, Rui H, Wang J, Lin S, He Y, Chen M, et al. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J 2006;25(8):1646-58.
17. Graham TA, Weaver C, Mao F, Kimelman D, Xu W. Crystal structure of a beta-catenin/Tcf complex. Cell 2000;103(6):885-96.
18. Feixiong C, Weihua L, Yadi Z, Jie S, Zengrui W, Guixia L, et al. Classification of Cytochrome P450 Inhibitors and non-Inhibitors using combined classifiers. J Chem Inf Model 2012;52:3099-105.
19. Morris GM, Huey R, Olson AJ. Using autodock for ligand-receptor docking. Curr Protoc Bioinformatics 2008;Chapter 8:Unit 8.14.
20. James C, William GD, Adi FG, John DM, James BM Evaluation of a tetrazolium-based Semi automated colorimetric assay: Assessment of chemosensitivity testing. Cancer Res 1987;47:936-42.
21. Ana P, Franz B, Zeljan M, Ana, M, Biljana N, Nikola K. Identification and quantification of flavonoids and phenolic acids in burr parsley (Caucalis platycarpos L.), using high-performance liquid chromatography with diode array detection and electrospray ionization mass spectrometry. Molecules 2009;14:2466-90.
22. Gupta SR, Ravindranath B, Seshadri TR. Glucosides of Butea monosperma. Phytochemistry 1970;9:2231-5.
23. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and omputational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997;23:3â€‘25.
24. Lombardo F, Gifford E, Shalaeva MY. In silico ADME prediction: Data, models, facts and myths. Mini Rev Med Chem 2003;3(8):861-75.
25. Fidele NK, Lydia LL, James AM, Luc C, Owono O, Eugene M, et al. In silico drug metabolism and pharmacokinetic profiles of natural products from medicinal plants in the Congo basin. In Silico Pharmacol 2013;1:12.
26. Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics: Clinical implications. Clin Pharmacokinet 2003;42(1):59-98.
27. Cheng A, Merz KM Jr. Prediction of aqueous solubility of a diverse set of compounds using quantitative structure-property relationships. J Med Chem 2003;46(17):3572-80.
28. Azam F, Prasad MV, Thangavel N, Ali HI. Molecular docking studies of 1-(substituted phenyl)-3-(naphtha [1, 2-d] thiazol-2-yl) urea/thiourea derivatives with human adenosine A (2A) receptor. Bioinformation 2011;6(9):330-4.
29. Sehrawat A, Kumar V. Butein imparts free radical scavenging, anti-oxidative and proapoptotic properties in the flower extracts of Butea monosperma. Biocell 2012;36(2):63-71.
30. Choedon T, Shukla SK, Kumar V. Chemopreventive and anti-cancer properties of the aqueous extract of flowers of Butea monosperma. J Ethnopharmacol 2010;129(2):208-13.
31. Sekine S, Shibata T, Sakamoto M, Hirohashi S. Target disruption of the mutant beta-catenin gene in colon cancer cell line HCT116: Preservation of its malignant phenotype. Oncogene 2002;21(38):5906-11.
32. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 1998;58(6):1130-4.
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