Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6/COX-2 mediated JAK2/STAT3 signals as evidenced through data-based mathematical modeling.
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 1H 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.
['Raj|Vinit|V|', 'Bhadauria|Archana S|AS|', 'Singh|Ashok K|AK|', 'Kumar|Umesh|U|', 'Rai|Amit|A|', 'Keshari|Amit K|AK|', 'Kumar|Pranesh|P|', 'Kumar|Dinesh|D|', 'Maity|Biswanath|B|', 'Nath|Sneha|S|', 'Prakash|Anand|A|', 'Ansari|Kausar M|KM|', 'Jat|Jawahar L|JL|', 'Saha|Sudipta|S|']
D000818:Animals D003110:Colonic Neoplasms D051546:Cyclooxygenase 2 D005472:Fluorouracil D015850:Interleukin-6 D053614:Janus Kinase 2 D008297:Male D055432:Metabolomics D008962:Models, Theoretical D051381:Rats D017208:Rats, Wistar D050796:STAT3 Transcription Factor D015398:Signal Transduction D013830:Thiadiazoles
Colorectal cancer IL-6/COX-2 mediated JAK2/STAT3 Mathematical modeling 1,3,4-Thiadiazole derivatives (1)H NMR-based metabolomics