Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non‚Äêsmall cell lung cancer cells via Nrf2 inhibition
Authors: Xiangcui Chen
Zhicheng Yang
Qipeng Wu
Yang Yang
Huachao Li
Jiahao Zhang
Yueming Chen
Yanchao Deng
Luyong Zhang
Bing Liu
Journal: British Journal of Pharmacology (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: NSCLC; Flavonoids; Diosmetin; Anticancer properties; ROS production
Affiliations: Department of Clinical Pharmacy, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China., Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, China., Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, China., The Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China.

Abstract:  Background and purpose: Non-small-cell lung cancer (NSCLC) accounts for up to 80-85% of all lung cancers and has a disappointing prognosis. Flavonoids exert anticancer 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 its ability to enhance the antitumour activity of paclitaxel. Experimental approach: NSCLC cells, normal cell lines HLF-1 and BEAS-2B, and immunodeficient mice were chosen as models to study the effects of diosmetin. Changes in cell viability, apoptosis, and ROS were analysed by MTT assay, flow cytometry assay, and fluorescent probe DCFH-DA. Expression of proteins and mRNA was determined by Western blotting and real-time RT-PCR. Growth of xenografted tumours was measured. Spleens and other vital organs were analysed with histological and immunohistochemical techniques. 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 the PI3K/Akt/GSK-3Œ≤ 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 induced apoptosis and enhanced the efficacy of paclitaxel in NSCLC cells via ROS accumulation through disruption of the PI3K/Akt/GSK-3Œ≤/Nrf2 pathway. Therefore, diosmetin may be a promising candidate for adjuvant treatment of NSCLC. 

Retracted: No

PubPeer comments:
 The lung tissue images shown in figure 7d appear to inappropriately overlap. ***  *** Full figure 7  , 
 The authors may wish to also review figure 2h. The top two flow cytometry scattergraphs appear nearly identical. Below is original image (top) and then overlay marked with orange box showing cells nearly 100% cancel each other out (inside the orange box: gray = exact overlap, red = not exact overlap) ***  ***  , 
 Correction: https: bpspubs.onlinelibrary.wiley.com doi abs 10.1111 bph.14652 Images only below ***  ***  ***  ***  , 
 Erratum: [22 April 2021] . -------------------------------------------- In Figures 2h (Dio-5 u03bcM), 2d (right panel, control) and 4c (right panel, Dio + tBHQ), incorrect images were used for analysis. This has been corrected, and the analysis has changed very slightly. Figure 2h - BEAS-2B:  Figure 4c - H1299:  In addition, the images in Figures 2d (right panel, NAC group) and 4f (left panel, Dio + Nrf2 group) were mistakenly duplicated. The corrected figures are shown below. Figure 2d - A549: Right:  When assembling the panels for Figure 7d, one image from Con1-1(1) (as shown in the red square) was duplicated. This has now been corrected (as shown in the blue square). Figure 7d  The authors state that these unintentional mistakes do not affect the results and the conclusion of this study. , 
 An additional concern. It seems as if a band in Figure 2e and Figure 5b are the same after 180-degree rotation and horizontal stretch. They are described differently. It is difficult to understand how these transformations could occur by accident during figure assembly. There may be other examples of this elsewhere in the paper. ***  ,