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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 nuclear factor kappa B (NF-?B) regulates IL-8 expression, and while thymoquinone (TQ), the main active constituent of black seed essential oil, inhibits NF-kB activity, the precise mechanisms by which TQ regulates IL-8 expression 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 (PARP). TQ treatments inhibited expression of NF-?B and suppressed expression of IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS), and mRNAs of oxidative stress-related genes, NAD(P)H:quinoneoxidoreductase 1 (NQO1) and heme oxygenase-1 (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 TNF-related apoptosis-inducing ligand (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-kB 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.

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/content/papers/10.5339/qfarf.2013.BIOP-0155
2013-11-20
2019-10-17
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http://instance.metastore.ingenta.com/content/papers/10.5339/qfarf.2013.BIOP-0155
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