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Br J Pharmacol. 2019 Mar 1. doi: 10.1111/bph.14652. [Epub ahead of print]

Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition.

Chen X1,2,3, Wu Q1,2,3, Chen Y1,2,3, Zhang J1,2,3, Li H1,2,3, Yang Z1,2,3, Yang Y1,2,3, Deng Y1,2,3, Zhang L2,3,4, Liu B1,2,3.

Author information

1
Department of Clinical pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
2
Guangzhou key laboratory of construction and application of new drug screening model systems, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
3
Key Laboratory of New Drug Discovery and Evaluation of ordinary universities of Guangdong province, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
4
The Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.

Abstract

BACKGROUND AND PURPOSE:

Non-small cell lung cancer (NSCLC) accounts for up to 80-85% of all lung cancers with a disappointing prognosis. Flavonoids exert anti-cancer properties, mostly involving stimulation of ROS production without significant toxicity to normal cells. This study was aimed to delineate the effect of diosmetin, a natural flavonoid, on NSCLC cells and the ability to enhance the anti-tumour activity of paclitaxel.

EXPERIMENTAL APPROACH:

NSCLC cells, normal cell lines HLF-1 and BEAS-2B, as well as immunodeficient mice were chosen as a model to study the treatment effects. Changes in cell viability, apoptosis and ROS were analyzed by MTT assay, flow cytometry assay and fluorescent probe DCFH-DA. Molecule expression was determined by western blotting and real-time RT-PCR. Xenografted tumors, spleens and other vital organs were harvested and subjected to growth inhibition measurement, histological and immunohistochemical analyses.

KEY RESULTS:

Diosmetin induced selective apoptotic death in NSCLC cells, but spared normal cells, via ROS accumulation. Diosmetin induced ROS production in NSCLC cells probably via reducing Nrf2 stability through disruption of PI3K/Akt/GSK-3β pathway. The in vitro and in vivo xenograft studies showed that combined treatment of diosmetin and paclitaxel synergistically suppressed NSCLC cells. Histological analysis of vital organs showed no obvious toxicity of diosmetin, which matched our in vitro findings.

CONCLUSIONS AND IMPLICATIONS:

Diosmetin selectively induces apoptosis and enhances the paclitaxel efficacy in NSCLC cells via ROS accumulation through disruption of PI3K/Akt/GSK-3β/Nrf2 pathway. Therefore, diosmetin may be a promising candidate for NSCLC adjuvant treatment.

PMID:
30825187
DOI:
10.1111/bph.14652

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