Thymoquinone inhibits growth of human medulloblastoma cells by inducing oxidative stress and caspase-dependent apoptosis while suppressing NF-jB signaling and IL-8 expression

Ashour, Abdelkader Elbadawy Abbas and Ahmed, Atallah F. and Kumar, Ashok and Zoheir, Khairy M. A. and Aboul-Soud, Mourad A. and Ahmad, Sheikh F. and Attia, Sabry M. and Abd-Allah, Adel R. A. and Cheryan, Vino T. and Rishi, Arun K. (2016) Thymoquinone inhibits growth of human medulloblastoma cells by inducing oxidative stress and caspase-dependent apoptosis while suppressing NF-jB signaling and IL-8 expression. Thymoquinone inhibits growth of human medulloblastoma cells by inducing oxidative stress and caspase-dependent apoptosis while suppressing NF-jB signaling and IL-8 expression, 416 ((1-2)). pp. 141-155. ISSN 0300-8177 E-ISSN 1573-4919

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Abstract

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. The transcription factor NF-κB is overexpressed in human MB and is a critical factor for MB tumor growth. NF-κB is known to regulate the expression of interleukin-8 (IL-8), the chemokine that enhances cancer cell growth and resistance to chemotherapy. We have recently shown that thymoquinone (TQ) suppresses growth of hepatocellular carcinoma cells in part by inhibiting NF-κB signaling. Here we sought to extend these studies in MB cells and show that TQ suppresses growth of MB cells in a dose- and time-dependent manner, causes G2M cell cycle arrest, and induces apoptosis. TQ significantly increased generation of reactive oxygen species (ROS), while pretreatment of MB cells with the ROS scavenger N-acetylcysteine (NAC) abrogated TQ-induced cell death and apoptosis, suggesting that TQ-induced cell death and apoptosis are oxidative stress-mediated. TQ inhibitory effects were associated with inhibition of NF-κB and altered expression of its downstream effectors IL-8 and its receptors, the anti-apoptotic Bcl-2, Bcl-xL, X-IAP, and FLIP, as well as the pro-apoptotic TRAIL-R1, caspase-8, caspase-9, Bcl-xS, and cytochrome c. TQ-triggered apoptosis was substantiated by up-regulation of the executioner caspase-3 and caspase-7, as well as cleavage of the death substrate poly(ADP-ribose)polymerase. Interestingly, pretreatment of MB cells with NAC or the pan-caspase inhibitor zVAD-fmk abrogated TQ-induced apoptosis, loss of cyclin B1 and NF-κB activity, suggesting that these TQ-mediated effects are oxidative stress- and caspase-dependent. These findings reveal that TQ induces both extrinsic and intrinsic pathways of apoptosis in MB cells, and suggest its potential usefulness in the treatment of MB.

Item Type:	Article (Journal)
Additional Information:	8129/59658
Uncontrolled Keywords:	Medulloblastoma Daoy cells Thymoquinone Apoptosis NF-jB Cancer Intr
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Medicine > Department of Basic Medical
Depositing User:	Dr. Abdelkader Ashour
Date Deposited:	29 Nov 2017 14:37
Last Modified:	29 Nov 2017 14:37
URI:	http://irep.iium.edu.my/id/eprint/59658

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