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Document Type |
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Thesis |
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Document Title |
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IN VITRO AND IN VIVO INVESTIGATION OF ANTICANCER ACTIVITIES OF THYMOQUINONE ON THE EPIGENETIC CODE OF CANCER CELL الاستقصاء غير الحيوي والحيوي لأنشطة ثيموكينون مضادة سرطانياً على الشفرة فوق الجينية للخلية السرطانية |
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Subject |
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faculty of science |
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Document Language |
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Arabic |
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Abstract |
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The epigenetic silencing of tumour suppressor genes (TSGs) is a common finding in several solid and hematological tumors. Methylation of DNA and histone 3 as well as deacetylation of histone 3 mediated by DNA methyltransferase 1 (DNMT1), the histone 3 methyltransferase G9a and HDAC1 (histone deacetylase 1), respectively lead to epigenetic silencing of TSGs resulting in enhanced cell proliferation, metastasis and inhibition of apoptosis. Thymoquinone (TQ), the major biologically active compound of the black seed has demonstrated anticancer activities in various tumors by targeting several pathways. However, its effect on cancer cell epigenetic code is largely unknown. The present study aimed to investigate in vitro and in vivo the effect of TQ on the “epigenetic cancer signature” in the human breast cancer cell line (MDA-MB-468 cells) and the human acute lymphoblastic leukemia (Jurkat cells) and the related events. The present study also investigated the combinatorial cytotoxic effects of TQ and Difluoromethylornithine (DFMO), an irreversible inhibitor of the ornithine decarboxylase (ODC) enzyme on Jurkat cells and to determine the underlying mechanisms. We found that TQ inhibits cell proliferation and triggers apoptosis in both cancer cell lines in dose-dependent manner. RNA-sequencing showed that TQ-treated Jurkat cells resulted in the downregulation of key epigenetic players including the PHD and Ring Finger 1 (UHRF1), DNMT1, G9a and HDAC1, while several epigenetically regulated TSGs were up-regulated. Data obtained from RNA sequencing were confirmed using RT-qPCR in both cancer cells. We found that TQ decreases the expression of UHRF1, DNMT1, G9a and HDAC1 genes. Also, we showed that the combination of DFMO and TQ significantly reduced cell viability and resulted in significant synergistic effects on apoptosis when compared to either DFMO or TQ alone. RNA-sequencing showed that UHRF1, DNMT1 and HDAC1 were down-regulated in DFMO-treated Jurkat cells. The combination of DFMO and TQ dramatically decreased the expression of UHRF1, DNMT1 and HDAC1 genes compared to either DFMO or TQ alone. Interestingly, In line with the in vitro results, TQ was significantly effective as an antitumor agent in a DMBA-induced breast cancer in rats. TQ improved parameters of mammary carcinogenesis including liver and kidney morphology, body weight as well as percent of mortality as compared to rats with tumors without treatment with TQ.
These results suggest that TQ could be used as epigenetic drug that in vitor and in vivo target both DNA methylation and histone post-translational modifications which could be a promising strategy for the epigenetic therapy for both solid and blood tumors. These findings also suggest that the combination of DFMO and TQ could be a promising new strategy for the treatment of acute lymphoblastic leukemia by targeting the epigenetic code. |
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Supervisor |
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Dr. Mahmoud Alhosin |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1441 AH
2020 AD |
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Added Date |
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Thursday, July 23, 2020 |
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Researchers
| ريان عدنان شيخ | Sheikh, Ryan Adnan | Researcher | Doctorate | |
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