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Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Research Article

Intracellular Ellagic Acid Derived from Goat Urine DMSO Fraction (GUDF) Predicted as an Inhibitor of c-Raf Kinase

Author(s): Ajay Kumar Raj, Kiran Bharat Lokhande, Tanay Kondapally Prasad, Rasika Nandangiri, Sumitra Choudhary, Jayanta Kumar Pal and Nilesh Kumar Sharma*

Volume 24, Issue 2, 2024

Published on: 16 February, 2023

Page: [264 - 279] Pages: 16

DOI: 10.2174/1566524023666230113141032

Price: $65

Abstract

Background: Dietary chemicals and their gut-metabolized products are explored for their anti-proliferative and pro-cell death effects. Dietary and metabolized chemicals are different from ruminants such as goats over humans.

Methods: Loss of cell viability and induction of death due to goat urine DMSO fraction (GUDF) derived chemicals were assessed by routine in vitro assays upon MCF-7 breast cancer cells. Intracellular metabolite profiling of MCF-7 cells treated with goat urine DMSO fraction (GUDF) was performed using an in-house designed vertical tube gel electrophoresis (VTGE) assisted methodology, followed by LC-HRMS. Next, identified intracellular dietary chemicals such as ellagic acid were evaluated for their inhibitory effects against transducers of the c-Raf signaling pathway employing molecular docking and molecular dynamics (MD) simulation.

Results: GUDF treatment upon MCF-7 cells displayed significant loss of cell viability and induction of cell death. A set of dietary and metabolized chemicals in the intracellular compartment of MCF-7 cells, such as ellagic acid, 2-hydroxymyristic acid, artelinic acid, 10-amino-decanoic acid, nervonic acid, 2,4-dimethyl-2-eicosenoic acid, 2,3,4'- Trihydroxy,4-Methoxybenzophenone and 9-amino-nonanoic acid were identified. Among intracellular dietary chemicals, ellagic acid displayed a strong inhibitory affinity (-8.7 kcal/mol) against c-Raf kinase. The inhibitory potential of ellagic acid was found to be significantly comparable with a known c-Raf kinase inhibitor sorafenib with overlapping inhibitory site residues (ARG450, GLU425, TRP423, VA403).

Conclusion: Intracellular dietary-derived chemicals such as ellagic acid are suggested for the induction of cell death in MCF-7 cells. Ellagic acid is predicted as an inhibitor of c-Raf kinase and could be explored as an anti-cancer drug.

« Previous
[1]
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[3]
Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med 2015; 5(4): a006098.
[http://dx.doi.org/10.1101/cshperspect.a006098] [PMID: 25833940]
[4]
McCubrey JA, Abrams SL, Fitzgerald TL, et al. Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis. Adv Biol Regul 2015; 57: 75-101.
[http://dx.doi.org/10.1016/j.jbior.2014.09.016] [PMID: 25453219]
[5]
Kolch W, Heidecker G, Lloyd P, Rapp UR. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature 1991; 349(6308): 426-8.
[http://dx.doi.org/10.1038/349426a0] [PMID: 1992343]
[6]
Weber CK, Slupsky JR, Kalmes HA, Rapp UR. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res 2001; 61(9): 3595-8.
[PMID: 11325826]
[7]
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417(6892): 949-54.
[http://dx.doi.org/10.1038/nature00766] [PMID: 12068308]
[8]
Maurer G, Tarkowski B, Baccarini M. Raf kinases in cancer–roles and therapeutic opportunities. Oncogene 2011; 30(32): 3477-88.
[http://dx.doi.org/10.1038/onc.2011.160] [PMID: 21577205]
[9]
Weinstein-Oppenheimer CR, Henríquez-Roldán CF, Davis JM, et al. Role of the Raf signal transduction cascade in the in vitro resistance to the anticancer drug doxorubicin. Clin Cancer Res 2001; 7(9): 2898-907.
[PMID: 11555608]
[10]
Davis JM, Navolanic PM, Weinstein-Oppenheimer CR, et al. Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance. Clin Cancer Res 2003; 9(3): 1161-70.
[PMID: 12631622]
[11]
Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010; 140(2): 209-21.
[http://dx.doi.org/10.1016/j.cell.2009.12.040] [PMID: 20141835]
[12]
Leontovich AA, Zhang S, Quatraro C, et al. Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells. Int J Oncol 2012; 40(6): 1858-64.
[PMID: 22447278]
[13]
Romano D, Nguyen LK, Matallanas D, et al. Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling. Nat Cell Biol 2014; 16(7): 673-84.
[http://dx.doi.org/10.1038/ncb2986] [PMID: 24929361]
[14]
Khan N, Afaq F, Mukhtar H. Apoptosis by dietary factors: The suicide solution for delaying cancer growth. Carcinogenesis 2006; 28(2): 233-9.
[http://dx.doi.org/10.1093/carcin/bgl243] [PMID: 17151090]
[15]
Panteleev PV, Bolosov IA, Kalashnikov AÀ, et al. Combined antibacterial effects of goat cathelicidins with different mechanisms of action. Front Microbiol 2018; 9: 2983.
[http://dx.doi.org/10.3389/fmicb.2018.02983] [PMID: 30555455]
[16]
Sharma NK, Kumar A. Method of using goat urine DMSO fraction as anti-proliferative and apoptotic cell death compounds against cancer cells and composition thereof. IPA: 201821048505, 2019.
[17]
Kumar A, Swami S, Sharma NK. Distinct DNA metabolism and anti-proliferative effects of goat urine metabolites: An explanation for xeno-tumor heterogeneity. Curr Chem Biol 2020; 14(1): 48-57.
[http://dx.doi.org/10.2174/2212796814666200310102512]
[18]
Patra S, Pradhan B, Nayak R, et al. Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action. Phytomedicine 2021; 90: 153554.
[http://dx.doi.org/10.1016/j.phymed.2021.153554] [PMID: 34371479]
[19]
Cháirez-Ramírez MH, de la Cruz-López KG, García-Carrancá A. Polyphenols as antitumor agents targeting key players in cancer-driving signaling pathways. Front Pharmacol 2021; 12: 710304.
[http://dx.doi.org/10.3389/fphar.2021.710304] [PMID: 34744708]
[20]
Singh B, Iyer PKR. Mammary intraductal carcinoma in goats (Capra hircus). Vet Pathol 1972; 9(6): 441-6.
[http://dx.doi.org/10.1177/030098587200900604] [PMID: 29883991]
[21]
Löhr CV. One hundred two tumors in 100 goats (1987-2011). Vet Pathol 2013; 50(4): 668-75.
[http://dx.doi.org/10.1177/0300985812471544] [PMID: 23341420]
[22]
Acevedo C, Amaya C, López-Guerra JL. Rare breast tumors: Review of the literature. Rep Pract Oncol Radiother 2014; 19(4): 267-74.
[http://dx.doi.org/10.1016/j.rpor.2013.08.006] [PMID: 25061520]
[23]
González-Sarrías A, Espín JC, Tomás-Barberán FA, García-Conesa MT. Gene expression, cell cycle arrest and MAPK signalling regulation in Caco-2 cells exposed to ellagic acid and its metabolites, urolithins. Mol Nutr Food Res 2009; 53(6): 686-98.
[http://dx.doi.org/10.1002/mnfr.200800150] [PMID: 19437480]
[24]
Wang N, Wang ZY, Mo SL, et al. Ellagic acid, a phenolic compound, exerts anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer. Breast Cancer Res Treat 2012; 134(3): 943-55.
[http://dx.doi.org/10.1007/s10549-012-1977-9] [PMID: 22350787]
[25]
Wang L, Li W, Lin M, et al. Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis. Carcinogenesis 2014; 35(10): 2321-30.
[http://dx.doi.org/10.1093/carcin/bgu145] [PMID: 25023990]
[26]
Chen HS, Bai MH, Zhang T, Li GD, Liu M. Ellagic acid induces cell cycle arrest and apoptosis through TGF-β/Smad3 signaling pathway in human breast cancer MCF-7 cells. Int J Oncol 2015; 46(4): 1730-8.
[http://dx.doi.org/10.3892/ijo.2015.2870] [PMID: 25647396]
[27]
Gulzar M, Syed SB, Khan FI, et al. Elucidation of interaction mechanism of ellagic acid to the integrin linked kinase. Int J Biol Macromol 2019; 122: 1297-304.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.09.089] [PMID: 30227205]
[28]
Yousuf M, Shamsi A, Khan P, et al. Ellagic acid controls cell proliferation and induces apoptosis in breast cancer cells via inhibition of cyclin-dependent kinase 6. Int J Mol Sci 2020; 21(10): 3526.
[http://dx.doi.org/10.3390/ijms21103526] [PMID: 32429317]
[29]
Kim JY, Choi YJ, Kim HJ. Determining the effect of ellagic acid on the proliferation and migration of pancreatic cancer cell lines. Transl Cancer Res 2021; 10(1): 424-33.
[http://dx.doi.org/10.21037/tcr-20-2446] [PMID: 35116272]
[30]
Adnane L, Trail PA, Taylor I, Wilhelm SM. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 2006; 407: 597-612.
[http://dx.doi.org/10.1016/S0076-6879(05)07047-3] [PMID: 16757355]
[31]
Asami Y, Kakeya H, Komi Y, et al. Azaspirene, a fungal product, inhibits angiogenesis by blocking Raf-1 activation. Cancer Sci 2008; 99(9): 1853-8.
[http://dx.doi.org/10.1111/j.1349-7006.2008.00890.x] [PMID: 18637013]
[32]
Dineva IK, Zaharieva MM, Konstantinov SM, Eibl H, Berger MR. Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins. J Cancer Res Clin Oncol 2012; 138(11): 1909-17.
[http://dx.doi.org/10.1007/s00432-012-1271-6] [PMID: 22752602]
[33]
Kim JH, Kim JH, Kim SC, et al. Adenosine dialdehyde suppresses MMP-9-mediated invasion of cancer cells by blocking the Ras/Raf-1/ERK/AP-1 signaling pathway. Biochem Pharmacol 2013; 86(9): 1285-300.
[http://dx.doi.org/10.1016/j.bcp.2013.08.022] [PMID: 23994169]
[34]
Liu CY, Tseng LM, Su JC, et al. Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. Breast Cancer Res 2013; 15(4): 3254.
[http://dx.doi.org/10.1186/bcr3457] [PMID: 23938089]
[35]
Zhao YR, Li HM, Zhu M, et al. Non-benzoquinone geldanamycin analog, WK-88-1, induces apoptosis in human breast cancer cell lines. J Microbiol Biotechnol 2018; 28(4): 542-50.
[http://dx.doi.org/10.4014/jmb.1710.10063] [PMID: 29618179]
[36]
Jabbarzadeh Kaboli P, Ismail P, Ling KH. Molecular modeling, dynamics simulations, and binding efficiency of berberine derivatives: A new group of RAF inhibitors for cancer treatment. PLoS One 2018; 13(3): e0193941.
[http://dx.doi.org/10.1371/journal.pone.0193941] [PMID: 29565994]
[37]
Li Y, Liu C, Tang K, et al. Novel multi kinase inhibitor, T03 inhibits Taxol resistant breast cancer. Mol Med Rep 2018; 17(2): 2373-83.
[PMID: 29207185]
[38]
Dattachoudhury S, Sharma R, Kumar A, Jaganathan BG. Sorafenib inhibits proliferation, migration and invasion of breast cancer cells. Oncology 2020; 98(7): 478-86.
[http://dx.doi.org/10.1159/000505521] [PMID: 32434184]
[39]
Rezaei Adariani S, Buchholzer M, Akbarzadeh M, Nakhaei-Rad S, Dvorsky R, Ahmadian MR. Structural snapshots of RAF kinase interactions. Biochem Soc Trans 2018; 46(6): 1393-406.
[http://dx.doi.org/10.1042/BST20170528] [PMID: 30381334]
[40]
El-Fadl HMA, Hagag NM, El-Shafei RA, et al. Effective targeting of Raf-1 and its associated autophagy by novel extracted peptide for treating breast cancer cells. Front Oncol 2021; 11: 682596.
[http://dx.doi.org/10.3389/fonc.2021.682596] [PMID: 34513674]
[41]
Kumar A, Patel S, Bhatkar D, Sarode SC, Sharma NK. A novel method to detect intracellular metabolite alterations in MCF-7 cells by doxorubicin induced cell death. Metabolomics 2021; 17(1)
[http://dx.doi.org/10.1007/s11306-020-01755-2]
[42]
Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464(7287): 431-5.
[http://dx.doi.org/10.1038/nature08833] [PMID: 20130576]
[43]
Huang L, Hofer F, Martin GS, Kim SH. Structural basis for the interaction of Ras with RaIGDS. Nat Struct Biol 1998; 5(6): 422-6.
[http://dx.doi.org/10.1038/nsb0698-422] [PMID: 9628477]
[44]
Hicks SN, Jezyk MR, Gershburg S, Seifert JP, Harden TK, Sondek J. General and versatile autoinhibition of PLC isozymes. Mol Cell 2008; 31(3): 383-94.
[http://dx.doi.org/10.1016/j.molcel.2008.06.018] [PMID: 18691970]
[45]
Glatz G, Gógl G, Alexa A, Reményi A. Structural mechanism for the specific assembly and activation of the Extracellular Signal Regulated Kinase 5 (ERK5) module. J Biol Chem 2013; 288(12): 8596-609.
[http://dx.doi.org/10.1074/jbc.M113.452235] [PMID: 23382384]
[46]
Matsumoto T, Kinoshita T, Kirii Y, Tada T, Yamano A. Crystal and solution structures disclose a putative transient state of mitogen-activated protein kinase kinase 4. Biochem Biophys Res Commun 2012; 425(2): 195-200.
[http://dx.doi.org/10.1016/j.bbrc.2012.07.066] [PMID: 22828509]
[47]
Rigden DJ, Phillips SEV, Michels PAM, Fothergill-Gilmore LA. The structure of pyruvate kinase from Leishmania mexicana reveals details of the allosteric transition and unusual effector specificity 1 1Edited by I. A. Wilson. J Mol Biol. 1999; 291: pp. (3)615-35.
[http://dx.doi.org/10.1006/jmbi.1999.2918] [PMID: 10448041]
[48]
Tecle H, Shao J, Li Y, et al. Beyond the MEK-pocket: Can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK? Bioorg Med Chem Lett 2009; 19(1): 226-9.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.108] [PMID: 19019675]
[49]
Chen P, Lee NV, Hu W, et al. Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther 2016; 15(10): 2273-81.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0300] [PMID: 27496135]
[50]
Morris GM, Goodsell DS, Halliday RS, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19(14): 1639-62.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639:AID-JCC10>3.0.CO;2-B]
[51]
Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
[52]
Discovery Studio Visualizer v3.0. Accelrys Software Inc. 2010.
[53]
Schrödinger Release 2019-4: Desmond Molecular Dynamics System. New York, NY: D. E. Shaw Research 2019.
[54]
Schyman P, Liu R, Desai V, Wallqvist A. vNN web server for ADMET predictions. Front Pharmacol 2017; 8: 889.
[http://dx.doi.org/10.3389/fphar.2017.00889] [PMID: 29255418]
[55]
Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 2007; 14(3): 500-10.
[http://dx.doi.org/10.1038/sj.cdd.4402039] [PMID: 16990848]
[56]
Rockenfeller P, Koska M, Pietrocola F, et al. Phosphatidylethanolamine positively regulates autophagy and longevity. Cell Death Differ 2015; 22(3): 499-508.
[http://dx.doi.org/10.1038/cdd.2014.219] [PMID: 25571976]
[57]
Cheng M, Bhujwalla ZM, Glunde K. Targeting phospholipid metabolism in cancer. Front Oncol 2016; 6: 266.
[http://dx.doi.org/10.3389/fonc.2016.00266] [PMID: 28083512]

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