1. Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis
- Author
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Saleh A. Bakheet, Hala E. Abdel-Hamied, Arun K. Rishi, Quaiser Saquib, Adel R. A. Abd-Allah, Abdelrahman Z. Alzahrani, Shazia Jamal, Sabry M. Attia, Abdelkader E. Ashour, and Hesham M. Korashy
- Subjects
Chemokine ,Programmed cell death ,Carcinoma, Hepatocellular ,Clinical Biochemistry ,bcl-X Protein ,Apoptosis ,chemistry.chemical_compound ,Cell Line, Tumor ,Benzoquinones ,Humans ,Interleukin 8 ,Receptor ,Molecular Biology ,Thymoquinone ,Cell Proliferation ,biology ,Caspase 3 ,Cell growth ,Interleukin-8 ,Liver Neoplasms ,NF-kappa B ,Hep G2 Cells ,Cell Biology ,General Medicine ,Molecular biology ,Caspase 9 ,G2 Phase Cell Cycle Checkpoints ,Oxidative Stress ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Cancer cell ,biology.protein ,Cancer research ,M Phase Cell Cycle Checkpoints ,Poly(ADP-ribose) Polymerases ,Reactive Oxygen Species - Abstract
Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose- and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADP-ribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by up-regulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug.
- Published
- 2014