Identification of Herbacetin as L858R and T790M inhibitor in Breast Cancer
Main Article Content
Keywords
Docking, EGFR, L858R mutation, Nerium oleander, T790M mutation
Abstract
Epidermal Growth Factor Receptor plays a major role as an oncogene in breast cancer. Associated with unfavourable prognosis and relapse of disease, it is a major drug target for tyrosine kinase inhibitors. Currently used chemotherapeutic agents can only be used as a first line treatment option as it develops resistance against drug over a period of time. Phytochemicals identified from Nerium oleander were targeted against L858R and T790M mutation of EGFR in breast cancer. Among 203 phytochemicals identified, 93 passed the drug likeability test where the compounds can be used as drugs with minimal side effects. The phytochemicals were targeted against the native and mutant structure of EGFR retrieved from PDB. Among them, nine compounds including herbacetin expressed a good dock score and fit value against the mutations. Further, invitro cytotoxicity assay was conducted to confirm the result. Based on the dock score, fit value and the MTT results, herbacetin can be considered as an active inhibitor of L858R and T790M mutation.
References
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22. Levva, S., Kotoula, V., Kostopoulos, I., Manousou, K., Papadimitriou, C., Papadopoulou, K., Lakis, S., Koukoulias, K., Karavasilis, V., Pentheroudakis, G., Balassi, E., Zagouri, F., Kaklamanos, I. G., Pectasides, D., Razis, E., Aravantinos, G., Papakostas, P., Bafaloukos, D., Rallis, G., Gogas, H., … Fountzilas, G. (2017). Prognostic Evaluation of Epidermal Growth Factor Receptor (EGFR) Genotype and Phenotype Parameters in Triple-negative Breast Cancers. Cancer genomics & proteomics, 14(3), 181–195. https://doi.org/10.21873/cgp.20030
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25. Shahrokni, A., Rajebi, M. R. and Saif, M. W. (2009). Toxicity and efficacy of 5-fluorouracil and capecitabine in a patient with TYMS gene polymorphism: A challenge or a dilemma? Clinical Colorectal Cancer 8(4):231–234. https://doi.org/10.3816/CCC.2009.n.039
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33. Wei, X., Zhao, Z., Zhong, R., and Tan, X. (2021). A comprehensive review of herbacetin: From chemistry to pharmacological activities. Journal of ethnopharmacology, 279, 114356. https://doi.org/10.1016/j.jep.2021.114356
34. Wieduwilt, M. J. and Moasser, M. M. (2008). The epidermal growth factor receptor family: biology driving targeted therapeutics. Cellular and Molecular Life Sciences 65(10):1566–1584. https://doi.org/10.1007/s00018-008-7440-8
35. Yun, C. H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K. K., Meyerson, M., and Eck, M. J. (2008). The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proceedings of the National Academy of Sciences of the United States of America, 105(6), 2070–2075. https://doi.org/10.1073/pnas.0709662105
36. Zibbu, G., and Batra, A. (2010). A Review on Chemistry and Pharmacological activity of Nerium oleander L. J. Chem. Pharm. Res. 2(6):351-358.
2. Ali, R. and Wendt, M. K. (2017). The paradoxical functions of EGFR during breast cancer progression. Signal Transduction and Targeted Therapy 2:16042. https://doi.org/10.1038/sigtrans.2016.42
3. Alkahtani, S. A., Alshabi, A. M., Shaikh, I. A., Orabi, M. A., Abdel-Wahab, B. A., Walbi, I. A.,... and Hoskeri, J. H. (2022). In Vitro Cytotoxicity and Spectral Analysis-Based Phytochemical Profiling of Methanol Extract of Barleria hochstetteri, and Molecular Mechanisms Underlying Its Apoptosis-Inducing Effect on Breast and Lung Cancer Cell Lines. Separations, 9(10), 298. . https:// doi.org/10.3390/separations9100298
4. Al-Sanfi, A.E. (2020). Bioactive ingredients and pharmacological effects of Nerium oleander. 2IOSR Journal of Pharmacy 10(9): 19-32.
5. Becker, A., van Wijk, A., Smit, E. F. and Postmus, P. E. (2010). Side-effects of long-term administration of erlotinib in patients with non-small cell lung cancer. Journal of Thoracic Oncology 5(9):1477–1480. https://doi.org/10.1097/JTO.0b013e3181e981d9
6. Bhuvaneshwari, L., Arthy, E., Anitha, C., Dhanabalan, K., and Meena, M. (2007). Phytochemical analysis and Antibacterial activity of Nerium oleander. Ancient science of life 26(4), 24–28.
7. Budhiarko, D., Putra, T. P., Harsono, A. T., Masykura, N., Tjindarbumi, D., Widjajahakim, G. and Utomo, A. (2017). Frequency of L858R and L861Q EGFR mutation in triple-negative, luminal and HER2 of Indonesian breast cancers patients. Annals of Oncology 28: 10. https://doi.org/10.1093/annonc/mdx678.005
8. Cersosimo, R. J. (2006). Gefitinib: an adverse effects profile. Expert Opinion on Drug Safety 5(3):469–479. https://doi.org/10.1517/14740338.5.3.469
9. Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., Pinkston, C. M., John, E. M., Torres-Mejía, G., Hines, L. M., Giuliano, A. R., Wolff, R. K. and Slattery, M. L. (2013). Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study. International Journal of Molecular Epidemiology and Genetics 4(4):235–249.
10. Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7, 42717. https://doi.org/10.1038/srep42717
11. Delazar, A., Asnaashari, S., Nikkhah, E., and Asgharian, P. (2019). Phytochemical analysis and antiproliferative activity of the aerial parts of Scrophularia subaphylla. Research in pharmaceutical sciences, 14(3), 263–272. https://doi.org/10.4103/1735-5362.258495Ali, R. and Wendt, M. K. (2017). The paradoxical
functions of EGFR during breast cancer progression. Signal Transduction and Targeted Therapy 2:16042. https://doi.org/10.1038/sigtrans.2016.42
12. Farooqui, S., and Tyagi, T. (2018). Nerium oleander: It’s application in basic and applied sciences: a review. International Journal of Pharmacy and Pharmaceutical Sciences 10(3): 1-4. http://dx.doi.org/10.22159/ijpps.2018v10i3.22505
13. Gaurav, A. and Gautam, V. (2017). Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors. Iranian Journal of Pharmaceutical Research 16(3):910–923.
14. Gupta, V., and Mittal, P. (2010). Phytochemical and Pharmacological Potential of Nerium oleander: A review. International Journal of Pharmaceutical Sciences and Research 3: 21-27. http://dx.doi.org/10.13040/IJPSR.0975-8232.1(3).21-27
15. Hase, G. J., Deshmukh, K.K., Pokharkar, R.D., Gaje, T.R., Phatanagre, N.D. (2017). Phytochemical Studies on Nerium oleander L. Using GC-MS. International Journal of Pharmacognosy and Phytochemical Research 9(6); 885-891. DOI number: 10.25258/phyto.v9i6.8195
16. Hedger, G., Sansom, M. S. and Koldsø, H. (2015). The juxtamembrane regions of human receptor tyrosine kinases exhibit conserved interaction sites with anionic lipids. Scientific Reports 5:9198. https://doi.org/10.1038/srep09198
17. Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., & Sarkar, S. (2014). Drug resistance in cancer: an overview. Cancers, 6(3), 1769–1792. https://doi.org/10.3390/cancers6031769
18. Kannan, S., Venkatachalam, G., Lim, H. H., Surana, U. and Verma, C. (2018). Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket. Chemical Science 9(23):5212–5222. https://doi.org/10.1039/c8sc01262h
19. Kiran, C., and Prasad, D. N. (2014). A review on: Nerium oleander Linn.(Kaner). International Journal of Pharmacognosy and Phytochemical Research, 6(3), 593-597.
20. Kulkarni, A. R., Reddy, R. G., Marlewar, S. S., Wadikar, S. S., Jangle, V. M. and Kulkarni, A. P. (2014). Cancer- An intergrative approach by Ayurveda. International Journal of Experimental Pharmacology 3(6):47-51.
21. Kumar, A., Petri, E. T., Halmos, B., & Boggon, T. J. (2008). Structure and clinical relevance of the epidermal growth factor receptor in human cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 26(10), 1742–1751. https://doi.org/10.1200/JCO.2007.12.1178
22. Levva, S., Kotoula, V., Kostopoulos, I., Manousou, K., Papadimitriou, C., Papadopoulou, K., Lakis, S., Koukoulias, K., Karavasilis, V., Pentheroudakis, G., Balassi, E., Zagouri, F., Kaklamanos, I. G., Pectasides, D., Razis, E., Aravantinos, G., Papakostas, P., Bafaloukos, D., Rallis, G., Gogas, H., … Fountzilas, G. (2017). Prognostic Evaluation of Epidermal Growth Factor Receptor (EGFR) Genotype and Phenotype Parameters in Triple-negative Breast Cancers. Cancer genomics & proteomics, 14(3), 181–195. https://doi.org/10.21873/cgp.20030
23. Nasab, R. R., Mansourian, M., Hassanzadeh, F., and Shahlaei, M. (2018). Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in-silico and in-vitro cytotoxicity methods. Research in pharmaceutical sciences, 13(6), 509–522. https://doi.org/10.4103/1735-5362.245963
24. Pal, S., Kumar, V., Kundu, B., Bhattacharya, D., Preethy, N., Reddy, M. P., & Talukdar, A. (2019). Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors. Computational and structural biotechnology journal, 17, 291–310. https://doi.org/10.1016/j.csbj.2019.02.006
25. Shahrokni, A., Rajebi, M. R. and Saif, M. W. (2009). Toxicity and efficacy of 5-fluorouracil and capecitabine in a patient with TYMS gene polymorphism: A challenge or a dilemma? Clinical Colorectal Cancer 8(4):231–234. https://doi.org/10.3816/CCC.2009.n.039
26. Shien, K., Yamamoto, H., Soh, J., Miyoshi, S. and Toyooka, S. (2014). Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer. Acta Medica Okayama 68(4):191–200. https://doi.org/10.18926/AMO/52785
27. Singh, S., Sharma, B., Kanwar, S. S. and Kumar, A. (2016). Lead Phytochemicals for Anticancer Drug Development. Frontiers in Plant Science 7:1667. https://doi.org/10.3389/fpls.2016.01667
28. Sinha, S.N., and Biswas, K. (2016). A concise review on Nerium oleander L. - An important medicinal plant. Tropical Plant Research 3(2): 408–412.
29. Teng, Y. H., Tan, W. J., Thike, A. A., Cheok, P. Y., Tse, G. M., Wong, N. S., Yip, G. W., Bay, B. H. and Tan, P. H. (2011). Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Research 13(2):R35. https://doi.org/10.1186/bcr2857
30. Tetsu, O., Hangauer, M. J., Phuchareon, J., Eisele, D. W. and McCormick, F. (2016). Drug Resistance to EGFR Inhibitors in Lung Cancer. Chemotherapy 61(5):223–235. https://doi.org/10.1159/000443368
31. Türkmenoğlu, B. and Güzel, Y. (2018). Molecular docking and 4D-QSAR studies of metastatic cancer inhibitor thiazoles. Computational Biology and Chemistry 76:327–337. https://doi.org/10.1016/j.compbiolchem.2018.07.003
32. Wang, S., Cang, S. and Liu, D. (2016). Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. Journal of Haematology and Oncology 9:34. https://doi.org/10.1186/s13045-016-0268-z
33. Wei, X., Zhao, Z., Zhong, R., and Tan, X. (2021). A comprehensive review of herbacetin: From chemistry to pharmacological activities. Journal of ethnopharmacology, 279, 114356. https://doi.org/10.1016/j.jep.2021.114356
34. Wieduwilt, M. J. and Moasser, M. M. (2008). The epidermal growth factor receptor family: biology driving targeted therapeutics. Cellular and Molecular Life Sciences 65(10):1566–1584. https://doi.org/10.1007/s00018-008-7440-8
35. Yun, C. H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K. K., Meyerson, M., and Eck, M. J. (2008). The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proceedings of the National Academy of Sciences of the United States of America, 105(6), 2070–2075. https://doi.org/10.1073/pnas.0709662105
36. Zibbu, G., and Batra, A. (2010). A Review on Chemistry and Pharmacological activity of Nerium oleander L. J. Chem. Pharm. Res. 2(6):351-358.
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Apr 11, 2023
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Akhila Rachel James, Sakthidasan Jayaprakash, & Sherin Mathew. (2023). Identification of Herbacetin as L858R and T790M inhibitor in Breast Cancer. Journal of Population Therapeutics and Clinical Pharmacology, 30(6), 267–286. https://doi.org/10.47750/jptcp.2023.30.06.033
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