Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLC
Lung cancer, the second leading cause of cancer mortality, requires the development of novel therapeutic strategies due to emerging drug resistance and toxicity. With this objective, the present work explored the therapeutic potential of R. graveolens leaf extracts against EGFR_T790M-mediated drug r...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1570108/full |
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| author | Vikas Kumar Leena Chauhan Deepa Singh Akash Kumar Rajkumar Kulandaisamy Tushar Kushwaha Kamal Baswal Rajan Singh Saroj Kumar Shivajirao L. Gholap P. Hariprasad S. Babu Dadinaboyina Jagadeshwar R. Thota Deepak Sehgal Mohan B. Appaiahgari Krishna K. Inampudi |
| author_facet | Vikas Kumar Leena Chauhan Deepa Singh Akash Kumar Rajkumar Kulandaisamy Tushar Kushwaha Kamal Baswal Rajan Singh Saroj Kumar Shivajirao L. Gholap P. Hariprasad S. Babu Dadinaboyina Jagadeshwar R. Thota Deepak Sehgal Mohan B. Appaiahgari Krishna K. Inampudi |
| author_sort | Vikas Kumar |
| collection | DOAJ |
| description | Lung cancer, the second leading cause of cancer mortality, requires the development of novel therapeutic strategies due to emerging drug resistance and toxicity. With this objective, the present work explored the therapeutic potential of R. graveolens leaf extracts against EGFR_T790M-mediated drug resistance in NSCLC. To this end, we evaluated the functional and therapeutic potential of a panel of polar and non-polar solvent extracts using various in vitro assay systems. Among the extracts tested, EAE exhibited superior kinase inhibitory activity, which was more pronounced against the EGFR_T790M mutant phenotype. Accordingly, EAE exhibited a favorable cytotoxicity profile and potent growth inhibition of EGFR_T790M-positive NSCLC cells, as evident from its superior IC50 values in this cell type. Flow cytometry analysis further validated its inhibitory effects on the cell cycle and, well-supported by the data from the TUNEL assay, suggested induction of apoptosis in EAE-treated cells in a dose-dependent manner. Finally, mechanistic studies in EAE-treated cells showed that these outcomes were due to concentration-dependent inhibition of EGFR phosphorylation at Tyr1068 and Tyr1173. Importantly, this inhibition was consistently more pronounced in H1975 cells expressing the EGFR_T790M mutant phenotype. Further, pull-down assays, followed by mass spectrometry analysis, identified the most promising molecules within EAE. Together, the study highlighted the therapeutic potential of EAE from the leaves of Ruta graveolens for treating EGFR_T790M-mediated drug resistance in lung cancer. |
| format | Article |
| id | doaj-art-0c4276fd262c4f9aa7544ccdd6a60095 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-0c4276fd262c4f9aa7544ccdd6a600952025-08-20T03:53:42ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15701081570108Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLCVikas Kumar0Leena Chauhan1Deepa Singh2Akash Kumar3Rajkumar Kulandaisamy4Tushar Kushwaha5Kamal Baswal6Rajan Singh7Saroj Kumar8Shivajirao L. Gholap9P. Hariprasad10S. Babu Dadinaboyina11Jagadeshwar R. Thota12Deepak Sehgal13Mohan B. Appaiahgari14Krishna K. Inampudi15Department of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaCentre for Rural Development and Technology, Indian Institute of Technology Delhi, New Delhi, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar Institution of Eminence, Gautam Buddha Nagar, Uttar Pradesh, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar Institution of Eminence, Gautam Buddha Nagar, Uttar Pradesh, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaChemistry Department, Indian Institute of Technology Delhi, New Delhi, IndiaCentre for Rural Development and Technology, Indian Institute of Technology Delhi, New Delhi, IndiaDepartment of Analytical and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, IndiaDepartment of Analytical and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, IndiaDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar Institution of Eminence, Gautam Buddha Nagar, Uttar Pradesh, IndiaLaboratory for Multidisciplinary Research in Virology, Yenepoya (deemed to be University), Mangalore, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaLung cancer, the second leading cause of cancer mortality, requires the development of novel therapeutic strategies due to emerging drug resistance and toxicity. With this objective, the present work explored the therapeutic potential of R. graveolens leaf extracts against EGFR_T790M-mediated drug resistance in NSCLC. To this end, we evaluated the functional and therapeutic potential of a panel of polar and non-polar solvent extracts using various in vitro assay systems. Among the extracts tested, EAE exhibited superior kinase inhibitory activity, which was more pronounced against the EGFR_T790M mutant phenotype. Accordingly, EAE exhibited a favorable cytotoxicity profile and potent growth inhibition of EGFR_T790M-positive NSCLC cells, as evident from its superior IC50 values in this cell type. Flow cytometry analysis further validated its inhibitory effects on the cell cycle and, well-supported by the data from the TUNEL assay, suggested induction of apoptosis in EAE-treated cells in a dose-dependent manner. Finally, mechanistic studies in EAE-treated cells showed that these outcomes were due to concentration-dependent inhibition of EGFR phosphorylation at Tyr1068 and Tyr1173. Importantly, this inhibition was consistently more pronounced in H1975 cells expressing the EGFR_T790M mutant phenotype. Further, pull-down assays, followed by mass spectrometry analysis, identified the most promising molecules within EAE. Together, the study highlighted the therapeutic potential of EAE from the leaves of Ruta graveolens for treating EGFR_T790M-mediated drug resistance in lung cancer.https://www.frontiersin.org/articles/10.3389/fphar.2025.1570108/fullLung cancerNSCLCEGFR_T790M mutationRuta graveolensethyl acetate extract |
| spellingShingle | Vikas Kumar Leena Chauhan Deepa Singh Akash Kumar Rajkumar Kulandaisamy Tushar Kushwaha Kamal Baswal Rajan Singh Saroj Kumar Shivajirao L. Gholap P. Hariprasad S. Babu Dadinaboyina Jagadeshwar R. Thota Deepak Sehgal Mohan B. Appaiahgari Krishna K. Inampudi Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLC Frontiers in Pharmacology Lung cancer NSCLC EGFR_T790M mutation Ruta graveolens ethyl acetate extract |
| title | Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLC |
| title_full | Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLC |
| title_fullStr | Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLC |
| title_full_unstemmed | Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLC |
| title_short | Ethyl acetate extract of Ruta graveolens: a specific and potent inhibitor against the drug-resistant EGFR_T790M mutant in NSCLC |
| title_sort | ethyl acetate extract of ruta graveolens a specific and potent inhibitor against the drug resistant egfr t790m mutant in nsclc |
| topic | Lung cancer NSCLC EGFR_T790M mutation Ruta graveolens ethyl acetate extract |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1570108/full |
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