An appraisal of cinnamyl sulfonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells

Neetinkumar D. Reddy, M. H. Shoja, Subhankar Biswas, Pawan G. Nayak, Nitesh Kumar, C. Mallikarjuna Rao

Research output: Contribution to journalArticle

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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 μM). 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 α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-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-1α expression, where the compounds reduced the expression of induced HIF-1α. 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.

Original languageEnglish
Pages (from-to)112-124
Number of pages13
JournalChemico-Biological Interactions
Volume253
DOIs
Publication statusPublished - 25-06-2016

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Histone Deacetylase Inhibitors
Sulfonamides
Human Activities
Cells
Histone Deacetylases
Derivatives
Matrix Metalloproteinases
Enzyme inhibition
Neoplasms
Tubulin
Cell Migration Inhibition
Histones
Assays
Acetylation
Annexin A5
Enzymes
Western Blotting
Cell death
Gelatin
Cytotoxicity

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

@article{8c2243ab00224c16ace10a2ae7fdffc2,
title = "An appraisal of cinnamyl sulfonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells",
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 μM). 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 α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-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-1α expression, where the compounds reduced the expression of induced HIF-1α. 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.",
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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.; Shoja, M. H.; Biswas, Subhankar; Nayak, Pawan G.; Kumar, Nitesh; Rao, C. Mallikarjuna.

In: Chemico-Biological Interactions, Vol. 253, 25.06.2016, p. 112-124.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An appraisal of cinnamyl sulfonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells

AU - Reddy, Neetinkumar D.

AU - Shoja, M. H.

AU - Biswas, Subhankar

AU - Nayak, Pawan G.

AU - Kumar, Nitesh

AU - Rao, C. Mallikarjuna

PY - 2016/6/25

Y1 - 2016/6/25

N2 - 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 μM). 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 α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-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-1α expression, where the compounds reduced the expression of induced HIF-1α. 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.

AB - 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 μM). 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 α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-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-1α expression, where the compounds reduced the expression of induced HIF-1α. 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.

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