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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    • "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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    • "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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