Abstract

Reactive oxygen species (ROS) are either toxic in excess or essential for redox signalling at the physiological level, which is closely related to the site of generation. Xanthohumol (XN) is an important natural product of hops (Humulus lupulus L.) and was reported to induce ROS in mitochondria. While in the present study, our data indicate that NADPH oxidase (NOX) is another site. In human acute myeloid leukemia HL-60 cells, we first identified that cell proliferation was inhibited by XN without affecting viability, and this could be alleviated by the antioxidant N-acetyl-L-cysteine (NAC); cell cycles were blocked at G1 phase, apoptosis was induced in a dose-dependent manner, and malondialdehyde (MDA) content was upregulated. XN-induced ROS generation was detected by flow cytometry, which can be inhibited by diphenyleneiodonium chloride (DPI, a NOX inhibitor), while not by NG-methyl-L-arginine acetate (L-NMMA, a nitric oxide synthase inhibitor). The involvement of NOX in XN-induced ROS generation was further evaluated: immunofluorescence assay indicated subunits assembled in the membrane, and gp91phox knockdown with siRNA decreased XN-induced ROS. Human red blood cells (with NOX, without mitochondria) were further selected as a cell model, and the XN-induced ROS and DPI inhibiting effects were found again. In conclusion, our results indicate that XN exhibits antiproliferation effects through ROS-related mechanisms, and NOX is a source of XN-induced ROS. As NOX-sourced ROS are critical for phagocytosis, our findings may contribute to the anti-infection and anti-inflammatory effect of XN.

Highlights

  • Reactive oxygen species (ROS) play a dual role in the initiation, development, suppression, and treatment of cancer [1, 2], and many anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production [2]

  • These results indicated that XN inhibited cell proliferation through an oxidative stressrelated mechanism, and this was further confirmed by the elevated MDA content under 10 μM XN treatment (Figure 1(e))

  • The results indicated that G1 phase cell cycle arrest (Figures 1(f) and 1(g)) and apoptosis (Figures 1(h) and 1(i)) were both induced by XN in a dose-dependent manner

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Summary

Introduction

ROS play a dual role in the initiation, development, suppression, and treatment of cancer [1, 2], and many anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production [2]. Many potential biological activities of XN have been reported, such as anti-infection against microorganisms including bacteria, viruses, fungi, and malarial protozoa [7], and anti-inflammatory [8], as well as the most widely studied anticancer properties [9,10,11]. Most of these activities correlate with the ROS-related mechanisms [9,10,11,12,13,14,15]. About the source of ROS induced by XN, it was reported, early in the year 2010, that XN induced superoxide anion radical formation via mitochondria [20], and another group further pointed out that XN induced ROS through inhibition of mitochondrial electron

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