TY - JOUR
T1 - 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
AU - Raj, Vinit
AU - Bhadauria, Archana S.
AU - Singh, Ashok K.
AU - Kumar, Umesh
AU - Rai, Amit
AU - Keshari, Amit K.
AU - Kumar, Pranesh
AU - Kumar, Dinesh
AU - Maity, Biswanath
AU - Nath, Sneha
AU - Prakash, Anand
AU - Ansari, Kausar M.
AU - Jat, Jawahar L.
AU - Saha, Sudipta
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - 1,3,4-Thiadiazole derivatives
KW - Colorectal cancer
KW - H NMR-based metabolomics
KW - IL-6/COX-2 mediated JAK2/STAT3
KW - Mathematical modeling
UR - https://www.scopus.com/pages/publications/85044275708
U2 - 10.1016/j.cyto.2018.03.026
DO - 10.1016/j.cyto.2018.03.026
M3 - Article
C2 - 29580751
AN - SCOPUS:85044275708
SN - 1043-4666
VL - 118
SP - 144
EP - 159
JO - Cytokine
JF - Cytokine
ER -
