Journal
CYTOKINE
Volume 118, Issue -, Pages 144-159Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2018.03.026
Keywords
1,3,4-Thiadiazole derivatives; Colorectal cancer; IL-6/COX-2 mediated JAK2/STAT3; Mathematical modeling; H-1 NMR-based metabolomics
Funding
- University Grants Commission (UGC), New Delhi, India [42-680/2013(SR)]
- Department of Science and Technology (DST), India for DST-SERB project [DST/SB/EMEQ-320/2014]
- Babasaheb Bhimrao Ambedkar University (BBAU), Lucknow, India
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We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through H-1 NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.
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