In Vitro and in Vivo Evaluation of Novel Cinnamyl Sulfonamide Hydroxamate Derivative Against Colon Adenocarcinoma

Reddy, Neetinkumar D and Shoja, MH and Jayashree, BS and Nayak, Pawan G and Kumar, Nitesh and Prasad, Ganga V and Pai, Sreedhara KR and Rao, Mallikarjuna C (2015) In Vitro and in Vivo Evaluation of Novel Cinnamyl Sulfonamide Hydroxamate Derivative Against Colon Adenocarcinoma. Chemico-Biological Interactions, 233. pp. 81-94.

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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 lM. 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 lM) 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-a, 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.

Item Type: Article
Uncontrolled Keywords: Colon cancer; Cinnamic acid; HDAC; Apoptosis; Caspase 3/7; 1,2-Dimethyl hydrazine (DMH)
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Manipal
Date Deposited: 23 Apr 2015 05:01
Last Modified: 23 Apr 2015 05:01
URI: http://eprints.manipal.edu/id/eprint/142498

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