Synthesis, characterization, and evaluation of Cd[L-proline]2, a novel histone deacetylase inhibitor that induces epigenetic modification of histone deacetylase isoforms in A549 cells

Summary Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with met...

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Published in:	Investigational new drugs Vol. 35; no. 6; pp. 691 - 705
Main Authors:	Chidambaram, Anusha, Sekar, Arunachalam, S.H., Kavya, Chidambaram, Ramesh Kumar, Arunachalam, Kalaiarasi, G.P., Senthilkumar, Vilwanathan, Ravikumar
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-12-2017 Springer Nature B.V
Subjects:	A549 Cells Aberration Acetylation Acridine orange Activation Anticancer properties Antitumor activity Apoptosis Apoptosis - drug effects BAX protein Cadmium Cadmium Compounds - chemistry Cadmium Compounds - pharmacology Cancer Caspase Caspase-8 Cell cycle Cell Cycle Checkpoints - drug effects Chromatin Coordination compounds Death receptors Drugs Epigenesis, Genetic Epigenetics Ethidium bromide Gelatinase A Gelatinase B Gene expression Gene silencing Histone Deacetylase 1 - antagonists & inhibitors Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - pharmacology Histones Humans Infrared radiation Inhibition Inhibitors Insulin Isoenzymes Isoforms Isomers Matrix metalloproteinases Medicine Medicine & Public Health Membrane potential Metal complexes Metastases NMR spectroscopy Oncology Pharmacology/Toxicology Preclinical Studies Proline Proline - chemistry Receptors Signal transduction Signaling Studies Synthesis Toxicity Epigenetics HDAC inhibitor Amino acids Metal complexes Hyperacetylation Apoptosis
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Summary:	Summary Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium–proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis. The synthesized compounds were characterized by UV, IR, NMR spectroscopy and elemental analysis. In-vitro cell toxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the 50% inhibitory concentration (IC 50 ; 2 μM) was obtained at 12 h. The morphological study at nuclear levels was performed by acridine orange/ethidium bromide (AO/EB) and Hoechst staining, and the results showed an association with cell cycle arrest at the G2/M phase. Both cadmium–proline complexes intensely inhibited HDAC activity at 2 μM concentration. Interestingly, Cd[L-proline] 2 was found to be a potent inhibitor for all HDAC isoforms, whereas Cd[D-proline] 2 inhibited only HDAC1 and 2. HDACi are novel chemotherapeutic drugs that induce hyperacetylation of histones H3 and H4, counteracting the aberrant repression of genes, such as insulin-like growth factor-binding protein 3 (IGFBP-3), p53, and p21. ERK/MAPK signaling pathway resulted in the downregulation of the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), contributing to the inhibition of metastasis in A549 cells. Apoptosis induction was accompanied by the activation of death receptors and their ligands which recruit initiator caspase 8, decrease in mitochondrial membrane potential (ΔΨm), as well as increased Bax/Bcl 2 ratio, followed by activation of caspases 9 and 3. Our finding suggests that Cd[L-proline] 2 complex accelerates epigenetic rearrangement by HDAC inhibition, which may be the key mechanism for its anticancer activity.
ISSN:	0167-6997 1573-0646
DOI:	10.1007/s10637-017-0489-1