An appraisal of Cinnamyl Sulfonamide Hydroxamate Derivatives (HDAC inhibitors) for Anti-cancer, Anti-angiogenic and Anti-metastatic Activities in Human Cancer Cells

Reddy, Neetinkumar D and Shoja, MH and Biswas, Subhankar and Nayak, Pawan G and Kumar, Nitesh and Rao, Mallikarjuna C (2016) An appraisal of Cinnamyl Sulfonamide Hydroxamate Derivatives (HDAC inhibitors) for Anti-cancer, Anti-angiogenic and Anti-metastatic Activities in Human Cancer Cells. Chemico-Biological Interactions, 253. pp. 112-124.

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Abstract

Multiple genetic mutations along with unusual epigenetic modifications play a major role in cancer development. Histone deacetylase (HDAC) enzyme overexpression observed in the majority of cancers is responsible for tumor suppressor gene silencing and activation of proto-oncogenes to oncogenes. Cinnamic acid derivatives exhibit anti-cancer potential through HDAC enzyme inhibition. We have synthesized a few cinnamyl sulfonamide hydroxamate derivatives (NMJ-1, -2 and -3) by already published in-house procedures and their purity, and chemical characterization were performed by NMR, mass spectrometry and elemental analysis. The anti-cancer activities were also evaluated against colon cancer.The rationale for synthesis was based on bioisosterism concept. To take the work forward, these compounds were considered for in vitro anti-angiogenic and anti-metastatic activities in cancer cells. The effectiveness of these compounds was determined by SRB assay. The compounds showed cancer cell cytotoxicity (IC50 range of 5.7 ± 0.43 to 20.5 ± 1.9 mM). The mechanism of compound-induced cell death involves an intrinsic apoptosis pathway which was supported by the following: increase in apoptotic index, arrest in cell cycle at G2/M phase, increase in annexin V binding and induction of p21Waf1/Cip1 expression in the treated cells. Further, their target modulating effect, measured as the expression of acetyl-H3 histone and acetyl a-tubulin was determined by Western blots. Hyper acetylation of H3 histone and a-tubulin were observed. Furthermore, increased expression of cleaved caspase-3, cleaved PARP, total Bad was estimated by ELISA. The anti-angiogenic effect was examined through cobalt (II) chloride (CoCl2)-induced HIF-1a expression, where the compounds reduced the expression of induced HIF-1a. In addition, their anti-metastatic ability was determined through phorbol-12-myristate-13- acetate (PMA)-induced expression of MMP-2 and -9 by Western blotting and gelatin zymography. Inhibition of malignant cell migration was assessed by scratch wound assay. The compounds showed a decrease in cell migration and inhibition of induced MMP-2 and MMP-9 expression. NMJ-2 exhibited comparable activity to that of standard SAHA. Our findings indicate that NMJ series of compound have potent in vitro anti-cancer, anti-angiogenic and anti-metastatic activity through HDAC enzyme inhibition.

Item Type: Article
Uncontrolled Keywords: Anti-angiogenic; Anti-metastatic; Apoptosis; HIF-1a; MMP-2 and MMP-9; HDA
Subjects: Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 07 Jun 2016 16:11
Last Modified: 07 Jun 2016 16:11
URI: http://eprints.manipal.edu/id/eprint/146317

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