Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer
Lung cancer is the leading type of malignancy in terms of occurrence and mortality in the global context. STAT3 is an oncogenic transcription factor that is persistently activated in many types of human malignancies, including lung cancer. In the present report, new oxadiazole conjugated indazoles w...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/9/368 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Vikas H. Malojirao Swamy S. Girimanchanaika Muthu K. Shanmugam Ankith Sherapura Dukanya Prashant K. Metri Vellingiri Vigneshwaran Arunachalam Chinnathambi Sulaiman Ali Alharbi Shobith Rangappa Chakrabhavi Dhananjaya Mohan Basappa Bettadathunga T. Prabhakar Kanchugarakoppal S. Rangappa |
| spellingShingle |
Vikas H. Malojirao Swamy S. Girimanchanaika Muthu K. Shanmugam Ankith Sherapura Dukanya Prashant K. Metri Vellingiri Vigneshwaran Arunachalam Chinnathambi Sulaiman Ali Alharbi Shobith Rangappa Chakrabhavi Dhananjaya Mohan Basappa Bettadathunga T. Prabhakar Kanchugarakoppal S. Rangappa Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer Biomedicines lung cancer antitumor STAT3 apoptosis |
| author_facet |
Vikas H. Malojirao Swamy S. Girimanchanaika Muthu K. Shanmugam Ankith Sherapura Dukanya Prashant K. Metri Vellingiri Vigneshwaran Arunachalam Chinnathambi Sulaiman Ali Alharbi Shobith Rangappa Chakrabhavi Dhananjaya Mohan Basappa Bettadathunga T. Prabhakar Kanchugarakoppal S. Rangappa |
| author_sort |
Vikas H. Malojirao |
| title |
Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer |
| title_short |
Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer |
| title_full |
Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer |
| title_fullStr |
Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer |
| title_full_unstemmed |
Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer |
| title_sort |
novel 1,3,4-oxadiazole targets stat3 signaling to induce antitumor effect in lung cancer |
| publisher |
MDPI AG |
| series |
Biomedicines |
| issn |
2227-9059 |
| publishDate |
2020-09-01 |
| description |
Lung cancer is the leading type of malignancy in terms of occurrence and mortality in the global context. STAT3 is an oncogenic transcription factor that is persistently activated in many types of human malignancies, including lung cancer. In the present report, new oxadiazole conjugated indazoles were synthesized and examined for their anticancer potential in a panel of cancer cell lines. Among the new compounds, 2-(3-(6-chloro-5-methylpyridin-3-yl)phenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole (CHK9) showed consistently good cytotoxicity towards lung cancer cells with IC<sub>50</sub> values ranging between 4.8–5.1 µM. The proapoptotic effect of CHK9 was further demonstrated by Annexin-FITC staining and TUNEL assay. In addition, the effect of CHK9 on the activation of STAT3 in lung cancer cells was examined. CHK9 reduced the phosphorylation of STAT3<sup>Y705</sup> in a dose-dependent manner. CHK9 had no effect on the activation and expression of JAK2 and STAT5. It also reduced the STAT3-dependent luciferase reporter gene expression. CHK9 increased the expression of proapoptotic (p53 and Bax) proteins and decreased the expression of the antiapoptotic (Bcl-2, Bcl-xL, BID, and ICAM-1) proteins. CHK9 displayed a significant reduction in the number of tumor nodules in the in vivo lung cancer model with suppression of STAT3 activation in tumor tissues. CHK9 did not show substantial toxicity in the normal murine model. Overall, CHK9 inhibits the growth of lung cancer cells and tumors by interfering with the STAT3 signaling pathway. |
| topic |
lung cancer antitumor STAT3 apoptosis |
| url |
https://www.mdpi.com/2227-9059/8/9/368 |
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doaj-2504a6e66d6946f9a80db7cb5307112d2020-11-25T03:40:09ZengMDPI AGBiomedicines2227-90592020-09-01836836810.3390/biomedicines8090368Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung CancerVikas H. Malojirao0Swamy S. Girimanchanaika1Muthu K. Shanmugam2Ankith Sherapura3Dukanya4Prashant K. Metri5Vellingiri Vigneshwaran6Arunachalam Chinnathambi7Sulaiman Ali Alharbi8Shobith Rangappa9Chakrabhavi Dhananjaya Mohan10Basappa11Bettadathunga T. Prabhakar12Kanchugarakoppal S. Rangappa13Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka 577203, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, IndiaDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, SingaporeMolecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka 577203, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, IndiaMolecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka 577203, IndiaDepartment of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaAdichunchanagiri Institute for Molecular Medicine, AIMS Campus, B. G. Nagar, Nagamangala Taluk, Mandya District 571448, IndiaDepartment of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, IndiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, IndiaMolecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka 577203, IndiaInstitution of Excellence, Vijnana Bhavan, University of Mysore, Mysore 570006, IndiaLung cancer is the leading type of malignancy in terms of occurrence and mortality in the global context. STAT3 is an oncogenic transcription factor that is persistently activated in many types of human malignancies, including lung cancer. In the present report, new oxadiazole conjugated indazoles were synthesized and examined for their anticancer potential in a panel of cancer cell lines. Among the new compounds, 2-(3-(6-chloro-5-methylpyridin-3-yl)phenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole (CHK9) showed consistently good cytotoxicity towards lung cancer cells with IC<sub>50</sub> values ranging between 4.8–5.1 µM. The proapoptotic effect of CHK9 was further demonstrated by Annexin-FITC staining and TUNEL assay. In addition, the effect of CHK9 on the activation of STAT3 in lung cancer cells was examined. CHK9 reduced the phosphorylation of STAT3<sup>Y705</sup> in a dose-dependent manner. CHK9 had no effect on the activation and expression of JAK2 and STAT5. It also reduced the STAT3-dependent luciferase reporter gene expression. CHK9 increased the expression of proapoptotic (p53 and Bax) proteins and decreased the expression of the antiapoptotic (Bcl-2, Bcl-xL, BID, and ICAM-1) proteins. CHK9 displayed a significant reduction in the number of tumor nodules in the in vivo lung cancer model with suppression of STAT3 activation in tumor tissues. CHK9 did not show substantial toxicity in the normal murine model. Overall, CHK9 inhibits the growth of lung cancer cells and tumors by interfering with the STAT3 signaling pathway.https://www.mdpi.com/2227-9059/8/9/368lung cancerantitumorSTAT3apoptosis |