Suresh, Rajaghatta N. and Jung, Young Y. and Mohan, C. D. and Shalini V. Gowda and Harsha, K. B. and Mantelingu, Kempegowda and Sethi, Gautam and Ahn, Kwang S. and Rangappa, K. S. (2023) A new triazolyl-indolo-quinoxaline induces apoptosis in gastric cancer cells by abrogating the STAT3/5 pathway through upregulation of PTPεC. Drug Development Research, 84 (8). pp. 1724-1738. ISSN 02724391
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A new triazolyl‐indolo‐quinoxaline induces apoptosis in gastric cancer cells by.pdf - Published Version Download (4MB) |
Abstract
Signal transducer and activator of transcription 3 (STAT3) and STAT5 are the transcription factors that have been studied extensively in relevance to the development of cancers in humans. Suppression of either STAT3 or STAT5-mediated signaling events has been demonstrated to be effective in inducing cytotoxicity in cancer cells. Herein, new hybrids of triazolyl-indolo-quinoxaline are synthesized and examined for their effect on the activation of STAT3 and STAT5 pathways in gastric cancer (GC) cells. Among the newly synthesized compounds, 2,3-difluoro-6-((1-(3-fluorophenyl)-1H-1,2,3-triazol-5-yl)methyl)-6H-indolo2,3-bquinoxaline (DTI) displayed selective cytotoxicity against GC cells over their normal counterpart. Flow cytometric analysis, annexin-V-fluorescein isothiocyanate staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, live and dead assay, and caspase activation experiments suggested DTI as a potent inducer of apoptosis. The mechanistic approach revealed that DTI imparts cytotoxicity via downregulating the phosphorylation of STAT3Y705 and STAT5Y694/699. DTI significantly reduced the nuclear pool of STAT3/STAT5 and reduced the DNA interaction ability of STAT3/STAT5 as evidenced by immunofluorescence and electrophoretic mobility shift assay. Further investigation revealed that inhibitory effects towards STAT proteins were mediated through the suppression of upstream kinases such as JAK1, JAK2, and Src. Treatment of GC cells with pervanadate counteracted the DTI-driven STAT3/STAT5 inhibition suggesting the involvement of tyrosine phosphatase. Upon DTI exposure, there was a significant upregulation in the mRNA and protein expression of PTPεC, which is a negative regulator of the JAK-STAT pathway. Knockdown of PTPεC suppressed the DTI-induced STATs inhibition in GC cells. Taken together, triazolyl-indolo-quinoxaline is presented as a new inhibitor of the STAT3/STAT5 pathway in GC cells. © 2023 Wiley Periodicals LLC.
| Item Type: | Article |
|---|---|
| Additional Information: | Cited by: 7 |
| Uncontrolled Keywords: | Apoptosis; DNA-Binding Proteins; Humans; Janus Kinases; Phosphorylation; Quinoxalines; Signal Transduction; STAT Transcription Factors; STAT3 Transcription Factor; STAT5 Transcription Factor; Stomach Neoplasms; Trans-Activators; Up-Regulation; 1 (1 aryl 1h 1,2,3 triazol 5 yl)methylindoline 2,3 dione; 2,3 difluoro 6 (1 phenyl 1h 1,2,3 triazol 5 yl)methyl 6h indolo2,3 bquinoxaline; 2,3 difluoro 6 1 (2 methoxyphenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 b quinoxaline; 2,3 difluoro 6 1 (2 methyl 4 nitrophenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 b quinoxaline; 2,3 difluoro 6 1 (3 fluorophenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 b quinoxaline; 2,3 difluoro 6 1 (3 fluorophenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 bquinoxaline; 2,3 difluoro 6 1 (3 methoxyphenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 b quinoxaline; 2,3 difluoro 6 1 (4 fluorophenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 b quinoxaline; 2,3 dimethyl 6 1 (2 methyl 2h indazol 7 yl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 b quinoxaline; 6 (1 phenyl 1h 1,2,3 triazol 5 yl)methyl 6h indolo2,3 bquinoxaline; 6 1 (2 methoxyphenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 bbiquinoxaline; 6 1 (2 methoxyphenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 bquinoxaline; 6 1 (2 methyl 2h indazol 7 yl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 bquinoxaline; 6 1 (3 methoxyphenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 bbiquinoxaline; 6 1 (3 methoxyphenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 bquinoxaline; 6 1 (4 fluorophenyl) 1h 1,2,3 triazol 5 yl]methyl] 6h indolo2,3 bquinoxaline; caspase; fluorescein isothiocyanate; indole derivative; Janus kinase 1; Janus kinase 2; lipocortin 5; messenger RNA; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; pervanadate; procaspase 3; protein kinase p60; protein tyrosine phosphatase epsilon; quinoxaline derivative; STAT3 protein; STAT5 protein; triazole derivative; unclassified drug; DNA binding protein; Janus kinase; quinoxaline derivative; STAT protein; STAT3 protein; STAT3 protein, human; STAT5 protein; transactivator protein; antineoplastic activity; apoptosis; Article; cancer cell; cancer inhibition; cell count; controlled study; DNA binding; drug cytotoxicity; drug structure; drug synthesis; flow cytometry; gel mobility shift assay; gene expression; gene knockdown; genetic transfection; human; human cell; immunofluorescence; JAK-STAT signaling; protein expression; protein function; protein phosphorylation; stomach cancer; transcription initiation; TUNEL assay; upregulation; apoptosis; metabolism; phosphorylation; signal transduction; stomach tumor; upregulation |
| Subjects: | C Chemical Science > Chemistry |
| Divisions: | Department of > Chemistry |
| Depositing User: | Mr Umendra uom |
| Date Deposited: | 01 Dec 2025 07:29 |
| Last Modified: | 17 Dec 2025 10:19 |
| URI: | http://eprints.uni-mysore.ac.in/id/eprint/18134 |
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