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In vitro and in vivo evaluation of novel cinnamyl sulfonamide hydroxamate derivative against colon adenocarcinoma.

Abstract
The potential of cinnamic acid as an anti-inflammatory and anti-cancer agent has been studied previously. In our investigation, novel bio-isosters of cinnamyl sulfonamide hydroxamate were synthesized, characterized and confirmed for their structure and evaluated for cytotoxicity. Three NCEs namely, NMJ-1, -2 and -3 showed cell-growth inhibition in 6 human cancer cell lines with IC50 at the range of 3.3±0.15-44.9±2.6 μM. The hydroxamate derivatives of cinnamyl sulfonamide are reported inhibitors of HDAC enzyme. Thus, the effectiveness of these molecules was determined by whole cell HDAC assay in HCT 116 cell line. NMJ-2 (0.41±0.01 μM) exhibited better enzyme inhibition (IC50) compared to SAHA (2.63±0.07). In order to evaluate induction of apoptosis by treatment, Hoechst 33342 and AO/EB nuclear staining methods were used. Further, cell cycle analysis, Annexin V binding and caspase 3/7 activation assays were performed by flow cytometry where NMJ-2 significantly arrested the cell cycle at G2/M phase, increased Annexin V binding to the cell surface and activation of caspase-3/7. Bax/Bcl-2 ratio was observed by Western blot and showed an increase with NMJ-2 treatment. This was comparable to standard SAHA. The acute toxicity study (OECD-425) showed that NMJ-2 was safe up to 2000 mg/kg in rats. 1,2-Dimethyl hydrazine (DMH) was used to produce experimental colon adenocarcinoma in Wistar rats. 5-FU and NMJ-2 (100 mg/kg p.o. and 10 mg/kg i.p. once daily for 21 days, respectively) were administered to the respective groups. Both treatments significantly reduced ACFs, adenocarcinoma count, TNF-α, IL-6, nitrite and nitrate levels in colonic tissue. Our findings indicate that NMJ-2 has potent anti-cancer activity against colon cancer, by acting through HDAC enzyme inhibition and activation of intrinsic mitochondrial apoptotic pathway, with additional anti-inflammatory activity.
AuthorsNeetinkumar D Reddy, M H Shoja, B S Jayashree, Pawan G Nayak, Nitesh Kumar, V Ganga Prasad, K Sreedhara R Pai, C Mallikarjuna Rao
JournalChemico-biological interactions (Chem Biol Interact) Vol. 233 Pg. 81-94 (May 25 2015) ISSN: 1872-7786 [Electronic] Ireland
PMID25824412 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Cinnamates
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Sulfonamides
  • cinnamic acid
  • Histone Deacetylases
Topics
  • Adenocarcinoma (drug therapy, metabolism, pathology)
  • Animals
  • Antineoplastic Agents (chemistry, therapeutic use)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cinnamates (chemistry, therapeutic use)
  • Colon (drug effects, metabolism, pathology)
  • Colonic Neoplasms (drug therapy, metabolism, pathology)
  • Female
  • Histone Deacetylase Inhibitors (chemistry, therapeutic use)
  • Histone Deacetylases (metabolism)
  • Humans
  • Hydroxamic Acids (chemistry, therapeutic use)
  • Models, Molecular
  • Rats, Wistar
  • Sulfonamides (chemistry, therapeutic use)

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