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1.
Int J Mol Sci ; 24(3)2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36768182

RESUMO

Minimizing side effects, overcoming cancer drug resistance, and preventing metastasis of cancer cells are of growing interest in current cancer therapeutics. Phytochemicals are being researched in depth as they are protective to normal cells and have fewer side effects. Hesperetin is a citrus bioflavonoid known to inhibit TGFß-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion of prostate cancer cells. Targeting epigenetic modifications that cause cancer is another class of upcoming therapeutics, as these changes are reversible. Global H3K27me3 levels have been found to be reduced in invasive prostate adenocarcinomas. Combining a demethylase inhibitor and a known anti-cancer phytochemical is a unique approach to targeting cancer to attain the aforementioned objectives. In the current study, we used an H3K27 demethylase (JMJD3/KDM6B) inhibitor to study its effects on TGFß-induced EMT in prostate cancer cells. We then gave a combined hesperetin and GSK-J4 treatment to the PC-3 and LNCaP cells. There was a dose-dependent increase in cytotoxicity and inhibition of TGFß-induced migration and invasion of prostate cancer cells after GSK-J4 treatment. GSK-J4 not only induced trimethylation of H3K27 but also induced the trimethylation of H3K4. Surprisingly, there was a reduction in the H3K9me3 levels. GSK-J4 alone and a combination of hesperetin and GSK-J4 treatment effectively inhibit the important hallmarks of cancer, such as cell proliferation, migration, and invasion, by altering the epigenetic landscape of cancer cells.


Assuntos
Histona Desmetilases , Neoplasias da Próstata , Humanos , Masculino , Histona Desmetilases/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Histona Desmetilases com o Domínio Jumonji , Transição Epitelial-Mesenquimal , Proliferação de Células , Neoplasias da Próstata/tratamento farmacológico
2.
Bioorg Med Chem Lett ; 29(23): 126683, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31627991

RESUMO

Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 µM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC50 value of 4.4 µM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.


Assuntos
Produtos Biológicos/uso terapêutico , Curcumina/síntese química , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Produtos Biológicos/farmacologia , Curcumina/análogos & derivados , Histona Desmetilases/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
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