Juglone, from Juglans mandshruica Maxim, inhibits growth and induces apoptosis in human leukemia cell HL-60 through a reactive oxygen species-dependent mechanism

Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, and Department of Infectious Diseases, First Hospital, Changchun, PR China.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association (Impact Factor: 2.9). 01/2012; 50(3-4):590-6. DOI: 10.1016/j.fct.2012.01.002
Source: PubMed


Juglone, a major chemical constituent of Juglans mandshruica Maxim, is a promising anticancer agent that has shown a strong activity against cancer cells in vitro. Our previous study showed that juglone inhibited the proliferation of HL-60 cells with an IC50 value ∼8 μM. To further explore the proapoptotic mechanism of juglone, we investigated the role of the reactive oxygen species (ROS) in the apoptosis induced by juglone in HL-60 cells. The generation of ROS was about 2 to 8-fold as compared to control cell after treatment with juglone (2, 4 and 8 μM) for 24 h. The glutathione (GSH) depletion was consistent with ROS generation after treatment with juglone. Reversal of apoptosis in antioxidants (NAC and catalase) pretreated cells indicated the involvement of ROS in juglone-induced apoptosis. The cleavage of PARP and procaspase-3 and -9, loss of mitochondrial membrane potential (△Ψm), and release of cytochrome c (Cyt c) and Smac induced by juglone were significantly blocked by NAC. NAC also prevented the inhibition the phosphorylation of Akt and mTOR proteins by juglone. Collectively, these results indicated that ROS played a significant role in the apoptosis induced by juglone in human leukemia cell HL-60.

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    • "Another natural compound named juglone (5-hydroxy-2- methyl-1,4-napthoquinone), a derivative of naphtoquinones, also possesses anti-inflammatory and anti-tumor properties. Anti-cancer effects of juglone, like other naphtoquinones, have been attributed to its ability to modulate oxidative stress and free radical formation through redox cycling and/or reaction with glutathione (Inbaraj and Chignell 2004; Xu et al. 2012). In addition to its ability to induce oxidative stress, juglone also affects some of the regulatory signals such as PI3K and pin1 (Hennig et al. 1998; Chae et al. 2012). "
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    ABSTRACT: Since reactive oxygen species (ROS) play diverse roles in cancer, modulating the redox status of cancerous cells seems to be a promising therapeutic approach. Oxidant-targeted therapy appears logical for intervention with the acquired adaptive response to oxidative stress in cancer. In this study, we investigated the cytotoxic effects of juglone (J) and tamoxifen (T) and also the combination of each with ascorbate (A): tamoxifen/ascorbate (TA) and/or juglone/ascorbate (JA) on MCF7 cancerous cells. The results revealed that the growth inhibitory effects of juglone and tamoxifen were each associated with enhanced levels of ROS production and lipid peroxidation. These effects were markedly intensified in tamoxifen/ascorbate and juglone/ascorbate co-treatments. On the other hand, the intracellular anti-oxidant components such as reduced glutathione (GSH), catalase, superoxide dismutase (SOD), and glutathione peroxidase significantly declined in cells subjected to combination treatments compared to that in cells exposed solely to tamoxifen, juglone, and the untreated control cells. In addition, ascorbate association induced more apoptotic and necrotic or necrotic-like cell death than cells treated with each drug alone. These results were further confirmed by comparing the Bax/Bcl2 ratio in combination-treated cells. Additionally, ascorbate was able to potentiate the cytotoxic effects of combination therapy via activation of ROS-responsive factors including Foxo family members.
    Full-text · Article · Nov 2015 · In Vitro Cellular & Developmental Biology - Animal
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    • "Juglone is a natural compound deriving from the Juglandaceae family, particularly Juglans nigra, whose toxic and growth-stunting effects are well known [11]. While Juglone was reported to induce generic oxidative stress in both healthy cells and cancer cell lines [12], we previously highlited the cytotoxic effect of its derivative 1 in inducing apoptotic cell death on human glioma cell lines [13] as a result of a screening on our in-house database. Starting from the discovery of this promising lead, the synthesis of novel naphthoquinone derivatives stems out with the aim of describing and comparing structureeactivity relationship (SAR) of Juglone and the obtained compounds by evaluating their effects on glioma cell death, allowing the enlightenment of the mechanism of action and, eventually, the optimization of the lead. "
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    ABSTRACT: This work was aimed to the development of a set of new naphtoquinone derivatives that can act against glioma. The compounds were tested in order to find out their ability to inhibit the growth of glioma cells, and the results of these assays were correlated with electrochemical analysis and NMR-based reoxidation kinetic studies, suggesting that a redox mechanism underlies and may explain the observed biological behavior. In addition to a full description of the synthetic pathways, electrochemistry, NMR and single crystal X-ray diffraction data are provided. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Full-text · Article · Apr 2015 · European Journal of Medicinal Chemistry
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    • "The same process may be involved in apigenin-induced ROS production in breast cancer cells. Oxidative stress caused by exposure to other phytochemicals such as juglone and a derivative of indole-3-carbinol is responsible for inhibiting Akt phosphorylation in leukemia cells (Bai et al., 2013; Xu et al., 2012). We similarly observed hypophosphorylation of Akt in apigenin-treated triple-negative breast cancer cells; however, this apigenin-induced blockade of Akt signaling was not due to oxidative stress since Akt phosphorylation was not rescued in the presence of a ROS scavenger. "
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    ABSTRACT: Epidemiological studies show that fruit- and vegetable-rich diets are associated with a reduced risk of developing certain forms of cancer, including breast cancer. In this study we demonstrate that a subcytotoxic concentration of apigenin, which is a flavone found at high concentrations in parsley, onions, grapefruit, oranges, and chamomile tea, inhibited DNA synthesis in a panel of human breast cancer cell lines (MDA-MB-231, MBA-MB-468, MCF-7, SK-BR-3). Decreased proliferation of MDA-MB-468 cells in the presence of apigenin was associated with G2/M phase cell cycle arrest and the production of reactive oxygen species. Apigenin-treated MDA-MB-468 cells also showed reduced phosphorylation of Akt (protein kinase B), which is an essential effector serine/threonine kinase in the phosphatidylinositide 3-kinase pathway that promotes tumor growth and progression. However, exposure to the antioxidant reduced glutathione failed to reverse apigenin-mediated inhibition of Akt phosphorylation and cell proliferation, indicating that these effects were not due to oxidative stress. Taken together, these findings suggest that low-dose apigenin has the potential to slow or prevent breast cancer progression.
    Full-text · Article · Oct 2014 · Experimental and Molecular Pathology
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