1. Novel dual-targeting anti-proliferative dihydrotriazine-chalcone derivatives display suppression of cancer cell invasion and inflammation by inhibiting the NF-κB signaling pathway.
- Author
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Gan FF, Zhang R, Ng HL, Karuppasamy M, Seah W, Yeap WH, Ong SM, Hadadi E, Wong SC, Chui WK, and Chew EH
- Subjects
- Animals, Breast Neoplasms pathology, Cell Line, Tumor, Cyclooxygenase 2 metabolism, Down-Regulation, Enzyme-Linked Immunosorbent Assay, Humans, Inflammation chemically induced, Inflammation Mediators metabolism, Lipopolysaccharides toxicity, Matrix Metalloproteinase 9 metabolism, Mice, Monocytes drug effects, Monocytes enzymology, Monocytes metabolism, Neoplasm Invasiveness prevention & control, Nitric Oxide Synthase Type II metabolism, RAW 264.7 Cells, Tetradecanoylphorbol Acetate pharmacology, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Chalcone pharmacology, Inflammation prevention & control, NF-kappa B metabolism, Signal Transduction drug effects, Triazines pharmacology
- Abstract
Chalcones present in edible plants possess anti-cancer and anti-inflammatory properties, with the Michael acceptor moiety reported to be responsible for their biological activities. In this study, two novel dihydrotriazine-chalcone compounds previously identified to exert anti-proliferative effects through dual-targeting of dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR), were evaluated for their anti-invasive and anti-inflammatory abilities. At non-lethal concentrations, the compounds suppressed in vitro migration of MDA-MB-231 breast carcinoma cells, which was correlated with a dose-dependent downregulation of phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) expression and secretion. At similar concentrations, these chalcone-based compounds suppressed expression of inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-stimulated murine macrophage-like RAW 264.7 cells, as well as tumor necrosis factor alpha (TNF-α) in LPS-stimulated human monocytes isolated from healthy donors. Mechanistically, inhibition of cancer cell invasion and inflammation by the compounds were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway, which corroborated with the reported mechanism of action of chalcones. Their abilities to target multiple biological mediators relevant to multi-step carcinogenesis and with bioactivities stronger than those of the parent chalcone scaffold have warranted dihydrotriazine-chalcone compounds as promising candidates for use in pharmacological intervention of aggressive cancers., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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