Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer

Malojirao, Vikas H. and Girimanchanaika, Swamy S. and Shanmugam, Muthu K. and Sherapura, Ankith and Dukanya and Metri, Prashant K. and Vigneshwaran, Vellingiri and Chinnathambi, Arunachalam and Alharbi, Sulaiman Ali and Rangappa, Shobith and Mohan, Chakrabhavi Dhananjaya and Basappa and Prabhakar, Bettadathunga T. and Rangappa, Kanchugarakoppal S. (2020) Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer. biomedicines, 8 (9). ISSN 2227-9059

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Abstract

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(50)values ranging between 4.8-5.1 mu M. 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(Y705)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.

Item Type: Article
Uncontrolled Keywords: lung cancer; antitumor; STAT3; apoptosis
Subjects: C Chemical Science > Biochemistry
Divisions: Department of > Biochemistry
Depositing User: Mr Umendra uom
Date Deposited: 06 Mar 2021 10:34
Last Modified: 06 Mar 2021 10:34
URI: http://eprints.uni-mysore.ac.in/id/eprint/15522

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