Validation of herbal flavonoids for breast cancer through pharmacological networking and in-vitro studies against MCF-7 and HepG2
Main Article Content
Keywords
breast cancer, molecular dynamics, DAVID, ethnobotany, Southern Punjab
Abstract
Breast cancer, the most common malignancy in developed countries, involves 12% of 20–34-year-old females. Herbal treatments for breast cancer are growing popular due to adverse effects of conventional treatments. Network pharmacology, ethnobotany, and in vitro studies have described bioactive compounds found in plants grown in Pakistan’s Southern Punjab for treating breast cancer. A quantitative analysis for selection of five plants was performed. Plant samples were collected, dried, prepared, and mounted on herbarium sheets. Phytochemicals were evaluated for chemical absorption, distribution, metabolism, excretion, and toxicity properties and target using SwissTargetPrediction. Potential breast cancer targets were identified via GeneCards database and database of gene disease association (DisGeNET). Enrichment analysis and protein interactions were exercised via database for annotation, visualization, and integrated discovery (DAVID) and Cytoscape. A drug compounds–genes–disease network found key genes for treatment, validated by molecular docking. The top three docking complexes withstood 200-nanoseconds (ns) molecular dynamics simulations in GROningen MAchine for Chemical Simulations (GROMACS) 2020, showing average Coulombic short-range interaction energies of apigenin with androgen receptor (-30.64 kJ/mol), apigenin with estrogen receptor 1 (ESR1; -62.35 kJ/mol), and luteolin with epidermal growth factor receptor (EGFR; -95.99 kJ/mol). Cytotoxicity of five plant extracts was analyzed on HepG2 and MCF7 cell lines. Liquid chromatography–mass spectrometry was performed for the compounds that had best half-maximal inhibitory concentration (IC50) value. This research investigates the anti-breast cancer mechanisms of plant flavonoids at molecular level.
References
Ahmed, M., Khan, M.A., Zafar, M., and Sultana, S. 2007. Treatment of common ailments by plant-based remedies among the people of district Attock (Punjab) of Northern Pakistan. African Journal of Traditional, Complementary and Alternative Medicines 4(1): 112–120. 10.4314/ajtcam.v4i1.31201
Al-Dalahmeh, Y., Al-Bataineh, N., Al-Balawi, S.S., Lahham, J.N., Al-Momani, I.F., Al-Sheraideh, M.S., Mayyas, A.S., Abu Orabi, S.T., and Al-Qudah, M.A. 2022. LC-MS/MS screening, total phenolic, flavonoid and antioxidant contents of crude extracts from three Asclepiadaceae species growing in Jordan. Molecules 27(3): 859. 10.3390/molecules27030859
Alley, M.C., Scudiero, D.A., Monks, A., Hursey, M.L., Czerwinski, M.J., Fine, D.L., Abbott, B.J., Mayo, J.G., Shoemaker, R.H., and Boyd, M.R. 1988. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Research 48(3): 589–601.
Asare, G.A., Afriyie, D., Ngala, R.A., Abutiate, H., Doku, D., Mahmood, S.A., and Rahman, H. 2015. Antiproliferative activity of aqueous leaf extract of Annona muricata L. on the prostate, BPH-1 cells, and some target genes. Integrative Cancer Therapies 4(1): 65–74. 10.1177/1534735414550198
Ashraf, M.A., Sayed, S., Bello, M., Hussain, N., Chando, R.K., Alam, S., and Hasan, M.K. 2022. CDK4 as a phytochemical-based anticancer drug target. Informatics in Medicine Unlocked 28: 100826. 10.1016/j.imu.2021.100826
Balick, M.J. 1996. Transforming ethnobotany for the new millennium. Annals of the Missouri Botanical Garden 83(1): 58–66. 10.2307/2399968
Bell, E.W., and Zhang, Y. 2019. DockRMSD: an open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism. Journal of Cheminformatics. 11(40): 1–9. 10.1186/s13321-019-0362-7
Bennett, B.C., and Prance, G.T. 2000. Introduced plants in the indigenous pharmacopoeia of Northern South America. Economic Botany 54: 90–102. 10.1007/BF02866603
Bhagya, N. 2023. Network pharmacology based investigation on the mechanism of tetrandrine against breast cancer. Phytomedicine Plus 3(1): 100381. 10.1016/j.phyplu.2022.100381
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., and Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 68(6): 394–424. 10.3322/caac.21492
Caiazza, F., Ryan, E.J., Doherty, G., Winter, D.C., and Sheahan, K. 2015. Estrogen receptors and their implications in colorectal carcinogenesis. Frontiers in Oncology 5: 19. 10.3389/fonc.2015.00019
Dagogo-Jack, I., and Shaw, A.T. 2018. Tumour heterogeneity and resistance to cancer therapies. Nature Reviews Clinical Oncology 15(2): 81–94. 10.1038/nrclinonc.2017.166
Darooei, M., Poornima, S., Salma, B.U., Iyer, G.R., Pujar, A.N., Annapurna, S., Shah, A., Maddali, S., and Hasan, Q. 2017. Pedigree and BRCA gene analysis in breast cancer patients to identify hereditary breast and ovarian cancer syndrome to prevent morbidity and mortality of disease in Indian population. Tumor Biology 39(2): 1010428317694303. 10.1177/1010428317694303
Eberhardt, J., Santos-Martins, D., Tillack, A.F., and Forli, S. 2021. AutoDock Vina 1.2. 0: new docking methods, expanded force field, and python bindings. Journal of Chemical Information and Modeling 61(8): 3891–3898. 10.1021/acs.jcim.1c00203
Fagbemi, K.O., Olajuyigbe, O.O., and Coopoosamy, R. 2023. Biogenic synthesis, characterization, antibacterial and antioxidant activities of silver nanoparticles mediated from Tamarindus indica Linn fruit pulp extract. Journal of Herbmed Pharmacology 12(4): 459–468. 10.34172/jhp.2023.43430
Farag, M.A., Huhman, D.V., Lei, Z., and Sumner, L.W. 2007. Metabolic profiling and systematic identification of flavonoids and isoflavonoids in roots and cell suspension cultures of Medicago truncatula using HPLC–UV–ESI–MS and GC–MS. Phytochemistry 68(3): 342–354. 10.1016/j.phytochem.2006.10.023
Giaquinto, A.N., Sung, H., Miller, K.D., Kramer, J.L., Newman, L.A., Minihan, A., Jemal, A., and Siegel, R.L. Breast cancer statistics, 2022. CA: A Cancer Journal for Clinicians 72(6): 524–541. 10.3322/caac.21754
Howard, K.S., Eldridge, D.J., and Soliveres, S. 2012. Positive effects of shrubs on plant species diversity do not change along a gradient in grazing pressure in an arid shrubland. Basic and Applied Ecology 13(2): 159–168. 10.1016/j.baae.2012.02.008
Huang, J., and MacKerell, A.D. Jr. 2013. CHARMM 36 all-atom additive protein force field: validation based on comparison to NMR data. Journal of Computational Chemistry 34(25): 2135–2145. 10.1002/jcc.23354
Huang, D.W., Sherman, B.T., and Lempicki, R.A. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4(1): 44–57. 10.1038/nprot.2008.211
Islam, M.K., Saha, S., Mahmud, I., Mohamad, K., Awang, K., Uddin, S.J., Rahman, M.M., and Shilpi, J.A. 2014. An ethnobotanical study of medicinal plants used by tribal and native people of Madhupur forest area, Bangladesh. Journal of ethnopharmacology 151(2): 921–930. 10.1016/j.jep.2013.11.056
Kadam, P., and Bhalerao, S. 2010. Sample size calculation. International Journal of Ayurveda Research 1(1): 55. 10.4103/0974-7788.59946
Karna, P., Gundala, S.R., Gupta, M.V., Shamsi, S.A., Pace, R.D., Yates, C., Narayan, S., and Aneja, R. 2011. Polyphenol-rich sweet potato greens extract inhibits proliferation and induces apoptosis in prostate cancer cells in vitro and in vivo. Carcinogenesis 32(12): 1872–1880. 10.1093/carcin/bgr215
Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B.A., Thiessen, P.A., Yu, B., and Zaslavsky, L. 2021. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Research 49(D1): D1388–D1395. 10.1093/nar/gkaa971
Krieger, E., Joo, K., Lee, J., Lee, J., Raman, S., Thompson, J., Tyka, M., Baker, D., and Karplus, K. 2009. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins: Structure, Function, and Bioinformatics 77(S9): 114–122. 10.1002/prot.22570
Li, A.P. 2001. Screening for human ADME/Tox drug properties in drug discovery. Drug Discovery Today 6(7): 357–366. 10.1016/S1359-6446(01)01712-3
Liu, C., Zoph, B., Neumann, M., Shlens, J., Hua, W., Li, L.J., Fei-Fei, L., Yuille, A., Huang, J., and Murphy, K. 2018. Progressive neural architecture search. In: Ferrari, V., Hebert, M., Sminchisescu, C., Weiss, Y. (eds). Proceedings of the European Conference on Computer Vision (ECCV) 2018. pp. 19–34. 10.1007/978-3-030-01246-5_2
Madan, A., Graham, R.A., Carroll, K.M., Mudra, D.R., Burton, L.A., Krueger, L.A., Downey, A.D. et al. 2003. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metabolism and Disposition. 31(4):421–31. 10.1124/dmd.31.4.421
Martinez-Perez, C., Ward, C., Cook, G., Mullen, P., McPhail, D., Harrison, D.J., and Langdon, S.P. 2014. Novel flavonoids as anti-cancer agents: mechanisms of action and promise for their potential application in breast cancer. Biochemical Society Transactions 42(4): 1017–1023. 10.1042/BST20140073
Masuda, K., Horinouchi, H., Tanaka, M., Higashiyama, R., Shinno, Y., Sato, J., Matsumoto, Y., Okuma, Y., Yoshida, T., Goto, Y., and Yamamoto, N. 2021. Efficacy of anti-PD-1 antibodies in NSCLC patients with an EGFR mutation and high PD-L1 expression. Journal of Cancer Research and Clinical Oncology 147: 245–251. 10.1007/s00432-020-03329-0
Milićević, D., Jurić, V., Stefanović, S., Baltić, T., and Janković, S. 2010. Evaluation and validation of two chromatographic methods (HPLC-Fluorescence and LC–MS/MS) for the determination and confirmation of ochratoxin A in pig tissues. Archives of Environmental Contamination and Toxicology 58: 1074–1081. 10.1007/s00244-009-9436-2
Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., and Olson, AJ. 2009. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry 30(16): 2785–2791. 10.1002/jcc.21256
Naponelli, V., Modernelli, A., Bettuzzi, S., and Rizzi, F. 2015. Roles of autophagy induced by natural compounds in prostate cancer. BioMed Research International 2015(1): 121826. 10.1155/2015/121826
Nurgali, K., Rudd, J.A., Was, H., and Abalo R. 2022. Cancer therapy: the challenge of handling a double-edged sword. Frontiers in Pharmacology 13: 1007762. 10.3389/fphar.2022.1007762
Rajakumar, N., and Shivanna, M.B. 2009. Ethno-medicinal application of plants in the eastern region of Shimoga district, Karnataka, India. Journal of Ethnopharmacology 126(1): 64–73. 10.1016/j.jep.2009.08.010
Rayan, A., Raiyn, J., and Falah, M. 2017. Nature is the best source of anticancer drugs: indexing natural products for their anticancer bioactivity. PloS One 12(11): e0187925. 10.1371/journal.pone.0187925
Santosh Kumar, M., Ankit, S., Gautam, D.N., and Anil Kumar, S. 2015. Biodiversity and indigenous uses of medicinal plant in the Chandra Prabha wildlife sanctuary, Chandauli district, Uttar Pradesh. International Journal of Biodiversity 2015(1): 394307. 10.1155/2015/394307
Sassa, T., Richter, W.W., Uda, N., Suganuma, M., Suguri, H., Yoshizawa, S., Hitota, M., and Fujiki, H. 1989. Apparent “activation” of protein kinases by okadaic acid class tumor promoters. Biochemical and biophysical research communications. 159(3):939–44. 10.1016/0006-291X(89)92199-2
Scarano, A., Chieppa, M., and Santino, A. 2018. Looking at flavonoid biodiversity in horticultural crops: a colored mine with nutritional benefits. Plants 7(4): 98. 10.3390/plants7040098
Schrödinger, L., and DeLano, W. 2020. PyMOL Available at: http://www.pymol.org/pymol (accessed: July 7, 2024).
Shahraki, S., Khajavirad, A., Shafei, M.N., Mahmoudi, M., and Tabasi, N.S. 2016. Effect of total hydroalcholic extract of Nigella sativa and its n-hexane and ethyl acetate fractions on ACHN and GP-293 cell lines. Journal of Traditional and Complementary Medicine6(1): 89–96. 10.1016/j.jtcme.2014.11.018
Stelzer, G., Plaschkes, I., Oz-Levi, D., Alkelai, A., Olender, T., Zimmerman, S., Twik, M., Belinky, F., Fishilevich, S., Nudel, R., and Guan-Golan, Y. 2016. VarElect: the phenotype-based variation prioritizer of the GeneCards Suite. BMC Genomics17: 195–206. 10.1186/s12864-016-2722-2
Su, X.L., Lin, R.C., Wong, S.K., Tsui, S.K., and Kwan, S.Y. 2003. Identification and characterisation of the Chinese herb Langdu by LC-MS/MS analysis. Phytochemical Analysis: An International Journal of Plant Chemical and Biochemical Techniques14(1): 40–47. 10.1002/pca.685
Tabuti, J.R., Lye, K.A., and Dhillion, S.S. 2003. Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration. Journal of Ethnopharmacology 88(1): 19–44. 10.1016/S0378-8741(03)00161-2
Ullah, A., Munir, S., Badshah, S.L., Khan, N., Ghani, L., Poulson, B.G., Emwas, A.H., and Jaremko, M. 2020. Important flavonoids and their role as a therapeutic agent. Molecules25(22): 5243. 10.3390/molecules25225243
Valdés-Tresanco, M.S., Valdés-Tresanco, M.E., Valiente, P.A., and Moreno, E. 2021. gmx_MMPBSA: a new tool to perform end-state free energy calculations with GROMACS. Journal of Chemical Theory and Computation17(10): 6281–6291. 10.1021/acs.jctc.1c00645
Vrhovsek, U., Rigo, A., Tonon, D., and Mattivi, F. 2004. Quantitation of polyphenols in different apple varieties. Journal of Agricultural and Food Chemistry 52(21): 6532–6538. 10.1021/jf049317z
Yang, H., Lou, C., Sun, L., Li, J., Cai, Y., Wang, Z., Li, W., Liu, G., and Tang, Y. 2019. admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics 35(6): 1067–1069. 10.1093/bioinformatics/bty707
Zhang, X., Shen, T., Zhou, X., Tang, X., Gao, R., Xu, L., Wang, L., Zhou, Z., Lin, J., and Hu, Y. 2020. Network pharmacology based virtual screening of active constituents of Prunella vulgaris L., and the molecular mechanism against breast cancer. Scientific Reports 10(1): 15730. 10.1038/s41598-020-72797-8
Al-Dalahmeh, Y., Al-Bataineh, N., Al-Balawi, S.S., Lahham, J.N., Al-Momani, I.F., Al-Sheraideh, M.S., Mayyas, A.S., Abu Orabi, S.T., and Al-Qudah, M.A. 2022. LC-MS/MS screening, total phenolic, flavonoid and antioxidant contents of crude extracts from three Asclepiadaceae species growing in Jordan. Molecules 27(3): 859. 10.3390/molecules27030859
Alley, M.C., Scudiero, D.A., Monks, A., Hursey, M.L., Czerwinski, M.J., Fine, D.L., Abbott, B.J., Mayo, J.G., Shoemaker, R.H., and Boyd, M.R. 1988. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Research 48(3): 589–601.
Asare, G.A., Afriyie, D., Ngala, R.A., Abutiate, H., Doku, D., Mahmood, S.A., and Rahman, H. 2015. Antiproliferative activity of aqueous leaf extract of Annona muricata L. on the prostate, BPH-1 cells, and some target genes. Integrative Cancer Therapies 4(1): 65–74. 10.1177/1534735414550198
Ashraf, M.A., Sayed, S., Bello, M., Hussain, N., Chando, R.K., Alam, S., and Hasan, M.K. 2022. CDK4 as a phytochemical-based anticancer drug target. Informatics in Medicine Unlocked 28: 100826. 10.1016/j.imu.2021.100826
Balick, M.J. 1996. Transforming ethnobotany for the new millennium. Annals of the Missouri Botanical Garden 83(1): 58–66. 10.2307/2399968
Bell, E.W., and Zhang, Y. 2019. DockRMSD: an open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism. Journal of Cheminformatics. 11(40): 1–9. 10.1186/s13321-019-0362-7
Bennett, B.C., and Prance, G.T. 2000. Introduced plants in the indigenous pharmacopoeia of Northern South America. Economic Botany 54: 90–102. 10.1007/BF02866603
Bhagya, N. 2023. Network pharmacology based investigation on the mechanism of tetrandrine against breast cancer. Phytomedicine Plus 3(1): 100381. 10.1016/j.phyplu.2022.100381
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., and Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 68(6): 394–424. 10.3322/caac.21492
Caiazza, F., Ryan, E.J., Doherty, G., Winter, D.C., and Sheahan, K. 2015. Estrogen receptors and their implications in colorectal carcinogenesis. Frontiers in Oncology 5: 19. 10.3389/fonc.2015.00019
Dagogo-Jack, I., and Shaw, A.T. 2018. Tumour heterogeneity and resistance to cancer therapies. Nature Reviews Clinical Oncology 15(2): 81–94. 10.1038/nrclinonc.2017.166
Darooei, M., Poornima, S., Salma, B.U., Iyer, G.R., Pujar, A.N., Annapurna, S., Shah, A., Maddali, S., and Hasan, Q. 2017. Pedigree and BRCA gene analysis in breast cancer patients to identify hereditary breast and ovarian cancer syndrome to prevent morbidity and mortality of disease in Indian population. Tumor Biology 39(2): 1010428317694303. 10.1177/1010428317694303
Eberhardt, J., Santos-Martins, D., Tillack, A.F., and Forli, S. 2021. AutoDock Vina 1.2. 0: new docking methods, expanded force field, and python bindings. Journal of Chemical Information and Modeling 61(8): 3891–3898. 10.1021/acs.jcim.1c00203
Fagbemi, K.O., Olajuyigbe, O.O., and Coopoosamy, R. 2023. Biogenic synthesis, characterization, antibacterial and antioxidant activities of silver nanoparticles mediated from Tamarindus indica Linn fruit pulp extract. Journal of Herbmed Pharmacology 12(4): 459–468. 10.34172/jhp.2023.43430
Farag, M.A., Huhman, D.V., Lei, Z., and Sumner, L.W. 2007. Metabolic profiling and systematic identification of flavonoids and isoflavonoids in roots and cell suspension cultures of Medicago truncatula using HPLC–UV–ESI–MS and GC–MS. Phytochemistry 68(3): 342–354. 10.1016/j.phytochem.2006.10.023
Giaquinto, A.N., Sung, H., Miller, K.D., Kramer, J.L., Newman, L.A., Minihan, A., Jemal, A., and Siegel, R.L. Breast cancer statistics, 2022. CA: A Cancer Journal for Clinicians 72(6): 524–541. 10.3322/caac.21754
Howard, K.S., Eldridge, D.J., and Soliveres, S. 2012. Positive effects of shrubs on plant species diversity do not change along a gradient in grazing pressure in an arid shrubland. Basic and Applied Ecology 13(2): 159–168. 10.1016/j.baae.2012.02.008
Huang, J., and MacKerell, A.D. Jr. 2013. CHARMM 36 all-atom additive protein force field: validation based on comparison to NMR data. Journal of Computational Chemistry 34(25): 2135–2145. 10.1002/jcc.23354
Huang, D.W., Sherman, B.T., and Lempicki, R.A. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4(1): 44–57. 10.1038/nprot.2008.211
Islam, M.K., Saha, S., Mahmud, I., Mohamad, K., Awang, K., Uddin, S.J., Rahman, M.M., and Shilpi, J.A. 2014. An ethnobotanical study of medicinal plants used by tribal and native people of Madhupur forest area, Bangladesh. Journal of ethnopharmacology 151(2): 921–930. 10.1016/j.jep.2013.11.056
Kadam, P., and Bhalerao, S. 2010. Sample size calculation. International Journal of Ayurveda Research 1(1): 55. 10.4103/0974-7788.59946
Karna, P., Gundala, S.R., Gupta, M.V., Shamsi, S.A., Pace, R.D., Yates, C., Narayan, S., and Aneja, R. 2011. Polyphenol-rich sweet potato greens extract inhibits proliferation and induces apoptosis in prostate cancer cells in vitro and in vivo. Carcinogenesis 32(12): 1872–1880. 10.1093/carcin/bgr215
Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B.A., Thiessen, P.A., Yu, B., and Zaslavsky, L. 2021. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Research 49(D1): D1388–D1395. 10.1093/nar/gkaa971
Krieger, E., Joo, K., Lee, J., Lee, J., Raman, S., Thompson, J., Tyka, M., Baker, D., and Karplus, K. 2009. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins: Structure, Function, and Bioinformatics 77(S9): 114–122. 10.1002/prot.22570
Li, A.P. 2001. Screening for human ADME/Tox drug properties in drug discovery. Drug Discovery Today 6(7): 357–366. 10.1016/S1359-6446(01)01712-3
Liu, C., Zoph, B., Neumann, M., Shlens, J., Hua, W., Li, L.J., Fei-Fei, L., Yuille, A., Huang, J., and Murphy, K. 2018. Progressive neural architecture search. In: Ferrari, V., Hebert, M., Sminchisescu, C., Weiss, Y. (eds). Proceedings of the European Conference on Computer Vision (ECCV) 2018. pp. 19–34. 10.1007/978-3-030-01246-5_2
Madan, A., Graham, R.A., Carroll, K.M., Mudra, D.R., Burton, L.A., Krueger, L.A., Downey, A.D. et al. 2003. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metabolism and Disposition. 31(4):421–31. 10.1124/dmd.31.4.421
Martinez-Perez, C., Ward, C., Cook, G., Mullen, P., McPhail, D., Harrison, D.J., and Langdon, S.P. 2014. Novel flavonoids as anti-cancer agents: mechanisms of action and promise for their potential application in breast cancer. Biochemical Society Transactions 42(4): 1017–1023. 10.1042/BST20140073
Masuda, K., Horinouchi, H., Tanaka, M., Higashiyama, R., Shinno, Y., Sato, J., Matsumoto, Y., Okuma, Y., Yoshida, T., Goto, Y., and Yamamoto, N. 2021. Efficacy of anti-PD-1 antibodies in NSCLC patients with an EGFR mutation and high PD-L1 expression. Journal of Cancer Research and Clinical Oncology 147: 245–251. 10.1007/s00432-020-03329-0
Milićević, D., Jurić, V., Stefanović, S., Baltić, T., and Janković, S. 2010. Evaluation and validation of two chromatographic methods (HPLC-Fluorescence and LC–MS/MS) for the determination and confirmation of ochratoxin A in pig tissues. Archives of Environmental Contamination and Toxicology 58: 1074–1081. 10.1007/s00244-009-9436-2
Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., and Olson, AJ. 2009. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry 30(16): 2785–2791. 10.1002/jcc.21256
Naponelli, V., Modernelli, A., Bettuzzi, S., and Rizzi, F. 2015. Roles of autophagy induced by natural compounds in prostate cancer. BioMed Research International 2015(1): 121826. 10.1155/2015/121826
Nurgali, K., Rudd, J.A., Was, H., and Abalo R. 2022. Cancer therapy: the challenge of handling a double-edged sword. Frontiers in Pharmacology 13: 1007762. 10.3389/fphar.2022.1007762
Rajakumar, N., and Shivanna, M.B. 2009. Ethno-medicinal application of plants in the eastern region of Shimoga district, Karnataka, India. Journal of Ethnopharmacology 126(1): 64–73. 10.1016/j.jep.2009.08.010
Rayan, A., Raiyn, J., and Falah, M. 2017. Nature is the best source of anticancer drugs: indexing natural products for their anticancer bioactivity. PloS One 12(11): e0187925. 10.1371/journal.pone.0187925
Santosh Kumar, M., Ankit, S., Gautam, D.N., and Anil Kumar, S. 2015. Biodiversity and indigenous uses of medicinal plant in the Chandra Prabha wildlife sanctuary, Chandauli district, Uttar Pradesh. International Journal of Biodiversity 2015(1): 394307. 10.1155/2015/394307
Sassa, T., Richter, W.W., Uda, N., Suganuma, M., Suguri, H., Yoshizawa, S., Hitota, M., and Fujiki, H. 1989. Apparent “activation” of protein kinases by okadaic acid class tumor promoters. Biochemical and biophysical research communications. 159(3):939–44. 10.1016/0006-291X(89)92199-2
Scarano, A., Chieppa, M., and Santino, A. 2018. Looking at flavonoid biodiversity in horticultural crops: a colored mine with nutritional benefits. Plants 7(4): 98. 10.3390/plants7040098
Schrödinger, L., and DeLano, W. 2020. PyMOL Available at: http://www.pymol.org/pymol (accessed: July 7, 2024).
Shahraki, S., Khajavirad, A., Shafei, M.N., Mahmoudi, M., and Tabasi, N.S. 2016. Effect of total hydroalcholic extract of Nigella sativa and its n-hexane and ethyl acetate fractions on ACHN and GP-293 cell lines. Journal of Traditional and Complementary Medicine6(1): 89–96. 10.1016/j.jtcme.2014.11.018
Stelzer, G., Plaschkes, I., Oz-Levi, D., Alkelai, A., Olender, T., Zimmerman, S., Twik, M., Belinky, F., Fishilevich, S., Nudel, R., and Guan-Golan, Y. 2016. VarElect: the phenotype-based variation prioritizer of the GeneCards Suite. BMC Genomics17: 195–206. 10.1186/s12864-016-2722-2
Su, X.L., Lin, R.C., Wong, S.K., Tsui, S.K., and Kwan, S.Y. 2003. Identification and characterisation of the Chinese herb Langdu by LC-MS/MS analysis. Phytochemical Analysis: An International Journal of Plant Chemical and Biochemical Techniques14(1): 40–47. 10.1002/pca.685
Tabuti, J.R., Lye, K.A., and Dhillion, S.S. 2003. Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration. Journal of Ethnopharmacology 88(1): 19–44. 10.1016/S0378-8741(03)00161-2
Ullah, A., Munir, S., Badshah, S.L., Khan, N., Ghani, L., Poulson, B.G., Emwas, A.H., and Jaremko, M. 2020. Important flavonoids and their role as a therapeutic agent. Molecules25(22): 5243. 10.3390/molecules25225243
Valdés-Tresanco, M.S., Valdés-Tresanco, M.E., Valiente, P.A., and Moreno, E. 2021. gmx_MMPBSA: a new tool to perform end-state free energy calculations with GROMACS. Journal of Chemical Theory and Computation17(10): 6281–6291. 10.1021/acs.jctc.1c00645
Vrhovsek, U., Rigo, A., Tonon, D., and Mattivi, F. 2004. Quantitation of polyphenols in different apple varieties. Journal of Agricultural and Food Chemistry 52(21): 6532–6538. 10.1021/jf049317z
Yang, H., Lou, C., Sun, L., Li, J., Cai, Y., Wang, Z., Li, W., Liu, G., and Tang, Y. 2019. admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics 35(6): 1067–1069. 10.1093/bioinformatics/bty707
Zhang, X., Shen, T., Zhou, X., Tang, X., Gao, R., Xu, L., Wang, L., Zhou, Z., Lin, J., and Hu, Y. 2020. Network pharmacology based virtual screening of active constituents of Prunella vulgaris L., and the molecular mechanism against breast cancer. Scientific Reports 10(1): 15730. 10.1038/s41598-020-72797-8
Article Sidebar
Published
Oct 1, 2025
Article Details
Section
Original Article
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
