Flavonoids potentiated anticancer activity of cisplatin in lung cancer by inhibiting histone deacetylases
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AbstractBackground:
Cisplatin is used in first-line chemotherapy of non-small cell lung cancer (NSCLC). However, its effectiveness is hindered by drug resistance, which is mediated by DNA repair, reduced apoptosis and insensitivity to cell cycle arrest. Combination of histone deacetylase inhibitors (HDACIs) and other anticancer drugs has emerged as a promising strategy to circumvent drug resistance. By facilitating histone acetylation, HDACIs upregulate tumour suppressor genes and downregulate drug resistance genes to kill cancer cells. Dietary flavonoids have been proposed to possess HDAC inhibitory effect.

Methods:
NSCLC cell lines (A549, H1650 and H1975) harbouring different oncogenic abnormalities were employed in the study. Western blot analysis was used to screen selected flavonoids for potential HDAC inhibition. Cell cycle arrest and apoptosis mediated by the HDAC-inhibiting flavonoids were evaluated by cell cycle analysis and Annexin-V apoptosis assay, respectively. Quantitative real-time PCR was employed to examine the expression of selected cell cycle-regulatory and apoptotic genes by the HDACIs. Regulation of transcriptional machinery by HDACIs was investigated by chromatin immunoprecipitation (ChIP) assay.

Results: Apigenin, a flavone-class flavonoid, was found to exhibit the strongest HDAC inhibitory effect. Therefore, combination of apigenin and cisplatin was investigated. Cisplatin-apigenin combination was found to produce significantly more S phase prolongation and G2/M cell cycle arrest, and apoptosis by inducing p21 and PUMA, respectively. Results from ChIP assay illustrated that apigenin reduced the binding of HDAC1 and increased histone acetylation at the gene promoter of p21 and PUMA, thus driving the observed transcription activation.

Conclusions: Apigenin was identified as a novel HDAC inhibitor. It was shown to potentiate the anticancer effect of cisplatin by inducing cell cycle arrest and apoptosis. In-depth investigation about the underlying mechanisms and optimum dosing sequence both in vitro and in vivo will be warranted to establish the usefulness of the new drug combination to circumvent drug resistance.
All Author(s) ListYan W, Wu MX, Tong CW, To KK
Name of Conference2019 NCRI Cancer Conference
Start Date of Conference03/11/2019
End Date of Conference05/11/2019
Place of ConferenceGlasgow
Country/Region of ConferenceGreat Britain
Year2019
LanguagesEnglish-United Kingdom
KeywordsHistone deacetylase inhibitors, drug combination

Last updated on 2020-02-06 at 11:18