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.
Animals
Colonic Neoplasms
/ drug therapy
Cyclooxygenase 2
/ metabolism
Fluorouracil
/ pharmacology
Interleukin-6
/ metabolism
Janus Kinase 2
/ metabolism
Male
Metabolomics
/ methods
Models, Theoretical
Rats
Rats, Wistar
STAT3 Transcription Factor
/ metabolism
Signal Transduction
/ drug effects
Thiadiazoles
/ pharmacology
(1)H NMR-based metabolomics
1,3,4-Thiadiazole derivatives
Colorectal cancer
IL-6/COX-2 mediated JAK2/STAT3
Mathematical modeling
Journal
Cytokine
ISSN: 1096-0023
Titre abrégé: Cytokine
Pays: England
ID NLM: 9005353
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
08
02
2018
revised:
19
03
2018
accepted:
19
03
2018
pubmed:
28
3
2018
medline:
9
7
2020
entrez:
28
3
2018
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 29580751
pii: S1043-4666(18)30112-1
doi: 10.1016/j.cyto.2018.03.026
pii:
doi:
Substances chimiques
Il6 protein, rat
0
Interleukin-6
0
STAT3 Transcription Factor
0
Stat3 protein, rat
0
Thiadiazoles
0
1,3,4-thiadiazole
14IAC3GH7G
Cyclooxygenase 2
EC 1.14.99.1
Ptgs2 protein, rat
EC 1.14.99.1
Jak2 protein, rat
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
144-159Informations de copyright
Copyright © 2018 Elsevier Ltd. All rights reserved.