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Document Type |
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Thesis |
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Document Title |
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Combination Therapy of Thymoquinone with Docetaxel Delivered by Nanoemulsion-based Borage as a Novel Approach in Treating Breast Cancer العلاج المدمج من الثيموكوينون والدوسيتاكسال المنقول بواسطة المستحلب النانومتري المعتمد على البوراج كنهج جديد في معالجة سرطان الثدي |
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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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Metastatic breast cancer is an advanced stage that is highly dependent on migration signaling pathways, though it remains unclear what mechanisms control the maintenance of tumorigenic cells that drives the migration and invasion processes. The drug delivery approach has vastly developed with the emergence of nanotechnology, particularly targeted nanoemulsions (NEs) which have the potential to improve the bioavailability of drugs leading to enhancement in their therapeutic efficiency. In this study, the potential role of borage oil-based nanoemulsion was investigated for the simultaneous administration of the microtubule inhibitors docetaxel (DTX) and thymoquinone (TQ) against MCF-7 and MDA-MB-231 and T47D human breast cancer cell lines. The NE was prepared by ultra-sonication and physically characterized using dynamic light scattering. The in vitro evaluation of cytotoxicity involved sulforhodamine B (SRB) assay, alongside a DNA fragmentation assessment. In addition, the distribution of cell cycle, apoptosis, autophagy, and breast cancer stem cells (BCSC) population were evaluated using flow cytometric analysis. Further molecular investigations of selected epithelial-mesenchymal transition genes expression were assessed utilizing a quantitative polymerase chain reaction (Q-PCR) technique. The optimum mean droplet size formulated for blank-NE-pH8 and the DTX+TQ /NE-pH8 were 56.04 ± 4.00 nm and 235.00 ± 10.00 nm, respectively. The optimum droplet sizes for blank-NE-pH7 and DTX+TQ /NE-pH7 were 117.3 ± 8.0 nm and 373 ± 6.8 nm, respectively. The half-maximal inhibitory concentration (IC50) of DTX+TQ /NE-pH8 was considerably lower than the free combination (DTX +TQ) when subjected to MCF-7 and MDA-MB-231 cells. The exposure to DTX plus TQ resulted in an antagonistic effect, whereas treatment with DTX+TQ /NE-pH8 resulted in a synergism effect on both tested cells. The observations derived from the cell death analysis of the DTX+TQ /NE-pH8 have revealed that autophagy can promote apoptosis with a possible mechanism that exerts a synergetic effect of cell death in MCF-7 and MDA-MB-231 cells. Moreover, the in vitro proliferation of T47D cells was significantly inhibited with a synergistic effect by the DTX+TQ /NE-pH7 formulation. In addition, a significant increase in apoptosis accompanied by the induction in autophagy was detected in T47D cells. DTX+TQ /NE-pH8 formulation inhibited the cellular proliferation by the G2/M phase and S-phase cell cycle arrest in MCF-7 and MDA-MB-231 cells, respectively. DTX+TQ /NE-pH8 caused a significant reduction in the cellular migration activity in MCF-7 and MDA-MB-231 cells as detected by the wound-healing assay. This observation could be mediated through the inhibition of BCSC, accompanied by marked down-regulation of SNAIL-1 and TWIST-1 expression. DTX+TQ /NE-pH7 arrested T47D cells at the G2/M phase, promoted the depletion of BCSC population, and inhibited the expression of TWIST-1 and ZEB-1. Overall, the results demonstrated that the co-delivery of DTX and TQ within NE formulation might be considered as a promising and effective therapeutic approach for breast cancer that enhances the DTX efficacy against human breast cancer cells by reducing its effective dose and thus reducing the associated toxicity that could prevent the intercellular signaling function of metastasis. |
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Supervisor |
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Prof. Mayson Husni Alkhatib |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1442 AH
2021 AD |
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Co-Supervisor |
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Prof. Hana Mohamed Gashlan |
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Added Date |
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Wednesday, June 23, 2021 |
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Researchers
| رغدة سالم باودود | Bawadud, Raghdah Salim | Researcher | Doctorate | |
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