Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung Cancer
Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGF<i>β</i> is one of the most powerful inducers of this transition, as it induces overexpression of the f...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1475 |
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| author | Elena Andreucci Kelly Bugatti Silvia Peppicelli Jessica Ruzzolini Matteo Lulli Lido Calorini Lucia Battistini Franca Zanardi Andrea Sartori Francesca Bianchini |
| author_facet | Elena Andreucci Kelly Bugatti Silvia Peppicelli Jessica Ruzzolini Matteo Lulli Lido Calorini Lucia Battistini Franca Zanardi Andrea Sartori Francesca Bianchini |
| author_sort | Elena Andreucci |
| collection | DOAJ |
| description | Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGF<i>β</i> is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer. |
| first_indexed | 2024-03-09T12:20:36Z |
| format | Article |
| id | doaj.art-289ca024219e44a186a8f437875bd6ee |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:20:36Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-289ca024219e44a186a8f437875bd6ee2023-11-30T22:40:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242147510.3390/ijms24021475Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung CancerElena Andreucci0Kelly Bugatti1Silvia Peppicelli2Jessica Ruzzolini3Matteo Lulli4Lido Calorini5Lucia Battistini6Franca Zanardi7Andrea Sartori8Francesca Bianchini9Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, ItalyDepartment of Food and Drug, University of Parma, Parco Area delle Scienze 27A, 43124 Parma, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, ItalyDepartment of Food and Drug, University of Parma, Parco Area delle Scienze 27A, 43124 Parma, ItalyDepartment of Food and Drug, University of Parma, Parco Area delle Scienze 27A, 43124 Parma, ItalyDepartment of Food and Drug, University of Parma, Parco Area delle Scienze 27A, 43124 Parma, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, ItalyGrowth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGF<i>β</i> is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer.https://www.mdpi.com/1422-0067/24/2/1475A549 lung cancer cellstransforming growth factor<i>β</i> (TGF<i>β</i>)αvβ6 integrin ligandsepithelial-mesenchymal transition (EMT)nintedanibmolecular conjugates |
| spellingShingle | Elena Andreucci Kelly Bugatti Silvia Peppicelli Jessica Ruzzolini Matteo Lulli Lido Calorini Lucia Battistini Franca Zanardi Andrea Sartori Francesca Bianchini Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung Cancer International Journal of Molecular Sciences A549 lung cancer cells transforming growth factor<i>β</i> (TGF<i>β</i>) αvβ6 integrin ligands epithelial-mesenchymal transition (EMT) nintedanib molecular conjugates |
| title | Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung Cancer |
| title_full | Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung Cancer |
| title_fullStr | Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung Cancer |
| title_full_unstemmed | Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung Cancer |
| title_short | Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGF<i>β</i>-Induced EMT in Human Non-Small Cell Lung Cancer |
| title_sort | nintedanib αvβ6 integrin ligand conjugates reduce tgf i β i induced emt in human non small cell lung cancer |
| topic | A549 lung cancer cells transforming growth factor<i>β</i> (TGF<i>β</i>) αvβ6 integrin ligands epithelial-mesenchymal transition (EMT) nintedanib molecular conjugates |
| url | https://www.mdpi.com/1422-0067/24/2/1475 |
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