TY - JOUR
T1 - 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates colon carcinogenesis via blockade of IL-6 mediated signals
AU - Mishra, Priyanka
AU - Raj, Vinit
AU - Bhadauria, Archana S.
AU - Singh, Ashok K.
AU - Rai, Amit
AU - Kumar, Pranesh
AU - Keshari, Amit K.
AU - De, Arnab
AU - Samanta, Amalesh
AU - Kumar, Umesh
AU - Kumar, Dinesh
AU - Maity, Biswanath
AU - Nath, Sneha
AU - Prakash, Anand
AU - Ansari, Kausar M.
AU - Saha, Sudipta
N1 - Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/4
Y1 - 2018/4
N2 - In this study, we investigated the in vivo antiproliferative activity of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) using albino Wistar rats. M1 was administered to DMH induced CRC rats at 10 and 25 mg/kg doses for 15 days. Various physiological, oxidative parameters, histopathology, ELISA, gene and protein expression studies were conducted to evaluate the anti-CRC potential of M1. The histopathology and biochemical tests indicated the protective action of M1 in DMH-induced colon cancer. ELISA confirms that M1 reduced the increased concentration of IL-6 more prominently than those of IL-2 and COX-2. Gene expression analysis revealed that M1 attenuated the increased mRNA over-expression of IL-6, JAK2 and STAT3. The result obtained from quantitative western blot analysis demonstrated that the CRC condition was produced by the IL-6 induced activation/phosphorylation of JAK2 and STAT3 and further down-regulated with M1 treatment. This evidence was supported well with the application of data-based mathematical modeling. Applying the fitted model, we predicted the quantitative behavior of STAT3 populations not accessible to experimental measurement. Later, 1H NMR based serum metabolic profiling was carried out using rat sera to investigate the impact of M1 on CRC-induced metabolic alterations. M1 showed its ability to restore the perturbed metabolites in CRC condition. Altogether, our study provided the first time evidence that M1 exhibits anti-CRC potential through the blockade of IL-6/JAK2/STAT3 oncogenic signaling.
AB - In this study, we investigated the in vivo antiproliferative activity of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) using albino Wistar rats. M1 was administered to DMH induced CRC rats at 10 and 25 mg/kg doses for 15 days. Various physiological, oxidative parameters, histopathology, ELISA, gene and protein expression studies were conducted to evaluate the anti-CRC potential of M1. The histopathology and biochemical tests indicated the protective action of M1 in DMH-induced colon cancer. ELISA confirms that M1 reduced the increased concentration of IL-6 more prominently than those of IL-2 and COX-2. Gene expression analysis revealed that M1 attenuated the increased mRNA over-expression of IL-6, JAK2 and STAT3. The result obtained from quantitative western blot analysis demonstrated that the CRC condition was produced by the IL-6 induced activation/phosphorylation of JAK2 and STAT3 and further down-regulated with M1 treatment. This evidence was supported well with the application of data-based mathematical modeling. Applying the fitted model, we predicted the quantitative behavior of STAT3 populations not accessible to experimental measurement. Later, 1H NMR based serum metabolic profiling was carried out using rat sera to investigate the impact of M1 on CRC-induced metabolic alterations. M1 showed its ability to restore the perturbed metabolites in CRC condition. Altogether, our study provided the first time evidence that M1 exhibits anti-CRC potential through the blockade of IL-6/JAK2/STAT3 oncogenic signaling.
KW - 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid
KW - Colorectal cancer
KW - IL-6/JAK2/STAT3
KW - Mathematical modeling
KW - NMR based metabolomics
UR - https://www.scopus.com/pages/publications/85041816012
U2 - 10.1016/j.biopha.2018.02.009
DO - 10.1016/j.biopha.2018.02.009
M3 - Article
C2 - 29448205
AN - SCOPUS:85041816012
SN - 0753-3322
VL - 100
SP - 282
EP - 295
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
ER -
