Subscribe to RSS
vHTS and 3D-QSAR for the Identification of Novel Phyto-inhibitors of Farnesyltransferase: Validation of Ascorbic Acid inhibition of Farnesyltransferase in an Animal Model of Breast Cancer
Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of attention in anti-cancer research over the past. In this study, phytochemicals from Curcuma longa L., Taraxacum officinale, and Spondias mombin plants were screened for their inhibitory potentials on the human farnesyltransferase. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the inhibition of farnesyltransferase was generated and the inhibition of farnesyltransferase by the hit, ascorbic acid was validated in an animal model of breast cancer. The lead compound, ascorbic acid makes extensive hydrogen bond interactions with key residues, lys-353, tyr-300, gly-290, leu-290 within the active site of farnesyltransferase. It downregulated the expression of FNTA mRNA in an animal model of breast cancer. The 3D-QSAR generated herein is robust, thoroughly validated, and should be employed in the pipelining of novel farnesyltransferase inhibitors. Ascorbic acid demonstrates its anticancer potentials through the inhibition of farnesyltransferase.
Key wordsFarnesyltransferase - Virtual high throughput screening - 3D-QSAR - Ascorbic acid - 7 - 12-dimethylbenz(a)anthracene (DMBA)
Received: 12 January 2021
Accepted: 08 March 2021
Article published online:
16 April 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Subramanian H, Gupta K, Ali H. Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases. The Journal of allergy and clinical immunology 2016; 138: 700-710
- 2 Gimple RC, Wang X. RAS: Striking at the Core of the Oncogenic Circuitry. Frontiers in oncology 2019; 9: 965
- 3 Bell IM. Inhibitors of farnesyltransferase: a rational approach to cancer chemotherapy?. Journal of medicinal chemistry 2004; 47: 1869-1878
- 4 Brunner TB, Hahn SM, Gupta AK. et al. Farnesyltransferase inhibitors: An overview of the results of preclinical and clinical investigations. Cancer research 2003; 63: 5656-5668
- 5 Karp JE, Lancet JE. Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics: targets & therapy 2008; 2: 491-500 https://doi.org/10.2147/btt.s3485
- 6 Dai X, Sun Y, Zhang T. et al. An overview on natural farnesyltransferase inhibitors for efficient cancer therapy. Journal of Enzyme Inhibition and Medicinal Chemistry 2020; 35: 1027-1044
- 7 Roa FJ, Peña E, Gatica M. et al. Therapeutic Use of Vitamin C in Cancer: Physiological Considerations. Frontiers in Pharmacology 2020; 11: 211
- 8 Ammon HPT, Safayhi H, Mack T. et al. Mechanism of antiinflammatory actions of curcumine and boswellic acids. Journal of Ethnopharmacology 1993; 38: I 13-I I9
- 9 Schütz K, Carle R, Schieber A. Taraxacum—A review on its phytochemical and pharmacological profile. Journal of Ethnopharmacology 2006; 107: 313-323 DOI: 10.1016/j.jep.2006.07.021.
- 10 Ayoka AO, Akomolafe RO, Akinsomisoye OS. , A & Ukponmwan O.E Medicinal and Economic Value of Spondias mombin. African Journal of Biomedical Research 2008; 11: 129-136
- 11 Lee J, Kim J, Koh JS. et al. Hydantoin derivatives as non-peptidic inhibitors of Ras farnesyl transferase. Bioorganic & medicinal chemistry letters 2006; 16: 1954-1956 DOI: 10.1016/j.bmcl.2005.12.074.
- 12 Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. Journal of Computational Chemistry 2010; 31: 455-461
- 13 Steinbeck C, Han Y, Kuhn S. et al. The Chemistry Development Kit (CDK): An Open-Source Java Library for Chemo- and Bioinformatics. Journal of Chemical Information and Modeling 2003; 43: 493-500
- 14 Ballabio D, Consonni V, Mauri A. et al. A novel variable reduction method adapted from space-filling designs. Chemometrics and Intelligent Laboratory Systems 2014; 136: 147-154
- 15 Todd MM, Arten P, Douglas MY. et al. Does Rational Selection of Training and Test Sets Improve the Outcome of QSAR Modeling?. Journal of Chemical Information and Modeling 2012; 52: 2570-2578
- 16 Metibemu DS, Akinloye OA, Akamo AJ. et al. Carotenoid isolates of Spondias mombin demonstrate anticancer effects in DMBA-induced breast cancer in Wistar rats through X-linked inhibitor of apoptosis protein (XIAP) antagonism and anti-inflammation. Journal of Food Biochemistry 2020; e13523
- 17 Bakalova R, Zhelev Z, Miller T. et al. Vitamin C versus Cancer: Ascorbic Acid Radical and Impairment of Mitochondrial Respiration?. Oxidative Medicine and Cellular Longevity 2020; 2020
- 18 Cárcamo JM, Pedraza A, Bórquez-Ojeda O. et al. Vitamin C is a kinase inhibitor: dehydroascorbic acid inhibits IkappaBalpha kinase beta. Molecular and cellular biology 2004; 24: 6645-6652 DOI: 10.1128/MCB.24.15.6645-6652.2004.
- 19 Fang Q, Naidu KA, Naidu KA. et al. Ascorbyl stearate inhibits cell proliferation and tumor growth in human ovarian carcinoma cells by targeting the PI3K/AKT pathway. Anticancer research 2006; 26: 203-209
- 20 Kar S, Roy K. How far can virtual screening take us in drug discovery?. Expert opinion on drug discovery 2013; 8: 245-261
- 21 Dybas JM, Madrid-Aliste CJ, Che FY. et al. Computational analysis and experimental validation of gene predictions in Toxoplasma gondii. PloS one 2008; 3: e3899 DOI: 10.1371/journal.pone.0003899.
- 22 Hevener KE, Zhao W, Ball DM. et al. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. Journal of chemical information and modeling 2009; 49: 444-460 DOI: 10.1021/ci800293n.
- 23 Sukumar N, Prabhu G, Saha P. Applications of genetic algorithms in QSAR/QSPR modeling. In: Applications of Metaheuristics in Process Engineering. 315-324. Springer, Cham; 2014
- 24 Tesfay D, Abrha S, Yilma Z. et al. Preparation, Optimization, and Evaluation of Epichlorohydrin Cross-Linked Enset (Ensete ventricosum (Welw.) Cheeseman) Starch as Drug Release Sustaining Excipient in Microsphere Formulation. BioMed research international 2020; 2020: 2147971 DOI: 10.1155/2020/2147971.
- 25 Mukherjee C, White H, Wuyts M. Econometrics and Data Analysis for Developing Countries. Routledge; 2013
- 26 Ganash MA. Anticancer potential of ascorbic acid and inorganic selenium on human breast cancer cell line MCF-7 and colon carcinoma HCT-116. Journal of cancer research and therapeutic 2020; 17: 122
- 27 Carr AC, Vissers MC, Cook JS. The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life. Frontiers in oncology 2014; 4: 283 DOI: 10.3389/fonc.2014.0028.
- 28 Klimant E, Wright H, Rubin D. et al. Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. Current oncology (Toronto, Ont.) 2018; 25: 139-148
- 29 Miyata M, Furukawa M, Takahashi K. et al. Mechanism of 7, 12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ. The Japanese Journal of Pharmacology 2001; 86: 302-309
- 30 Hakkak R, Holley AW, MacLeod SL. et al. Obesity promotes 7, 12-dimethylbenz (a) anthracene-induced mammary tumor development in female zucker rats. Breast Cancer Research 2005; 7: 1-7
- 31 Schmier S, Mostafa A, Haarmann T. et al. In silico prediction and experimental confirmation of HA residues conferring enhanced human receptor specificity of H5N1 influenza a viruses. Scientific reports 2015; 5: 1-16