Document Details
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Document Type |
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Thesis |
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Document Title |
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Combination Therapy of Topotecan with Carvacrol Delivered by Nanoemulsion-based Sesame Oil as a Novel Approach in Treating Cancer العلاج المدمج من التوبوتيكان والكارفاكرول المنقول بواسطة المستحلب النانومتري المعتمد على زيت السمسم كنهج جديد في معالجة السرطان |
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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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This study aimed to enhance topotecan (TOPO) cytotoxicity by minimizing its effective chemotherapeutic dose and thereby its side effects. To achieve this goal, different approaches were examined: TOPO was combined with the natural anticancer agent, carvacrol, either solubilized in water or loaded in sesame oil-based nanoemulsion (SO-NE); and TOPO, as lone treatment, was incorporated into SO-NE. After developing six SO-NE formulations, with different oil-to-surfactants ratios, by high-pressure ultrasonication technique, the produced SO-NE formulas were physically characterized by zeta-sizer, ultraviolet-spectrophotometer, transmission electron microscope (TEM), and in vitro drug release assay. The cytotoxic effects of different treatments were evaluated in six different cancer cell lines (HeLa cervical, HCT116 colon, MCF-7 breast, HepG2 liver, SKOV3 ovarian and A549 non-small cell lung) after 24 hours-incubation using crystal violet assay for growth inhibition determination, and Coomassie blue or DAPI fluorescent staining for cellular morphology assessment. Additionally, the cellular uptakes of TOPO were determined. According to the results of the physical characterizations for the SO-NE formulas, 3:15 (SO: surfactants ratio) SO-NE, was stable over time, had small particle size (115.20 ± 1.08 nm) and had the least surfactants percentage (15%) compared to the other SO-NEs. When TOPO loaded in SO-NE, its particles were stable, spherical, significantly decreased in size to (74.68 ± 7.38 nm) and exhibited beneficial TOPO prolonged and sustained release over 24 hours. When cells were treated with carvacrol/TOPO, HeLa and HCT116 resulted in 7.70- and 5.71-fold reduction in TOPO half maximal inhibitory concentration (IC50), respectively, while treatment of MCF7, HepG2, SKOV3, and A549 cancer cells resulted in 1.49-, 1.33-, 1.50- and 1.26-fold increase in TOPO IC50, respectively, relative to TOPO single treatment. In all cell lines tested, the effects of TOPO-loaded SO-NE formula on cancer cells proliferation, nuclear morphology, and TOPO cellular uptake, displayed significant anti-proliferation, considerable decreased IC50 and clear apoptotic changes, which may be due to the enhanced cellular uptake of TOPO. The mechanisms of cell death were assessed by measuring inflammatory interleukin-6, autophagy LC-3 and caspase-3 levels. In MCF-7 and HepG2 cells, the cytotoxicity was attributed to the anti-inflammatory effect, and to the induction of type I apoptotic and type II autophagic cell death. In HeLa cells, although the apoptotic induction mechanism was also through both types of cell death (I and II), an anti-inflammatory effect was not noticed. In HCT116 cells, SO-NE enhanced the sensitivity of cells to TOPO via autophagy inhibition, in addition to the anti-inflammatory effect and the induction of type 1 apoptosis by increasing caspase-3 levels in comparison with control. However, carvacrol addition to the TOPO-loaded SO-NE led to a significant increase in IC50 values in all cell lines relative to TOPO-loaded SO-NE treatment due to phase separation. In conclusion, carvacrol enhanced TOPO cytotoxicity and cellular uptake only in HeLa and HCT116 cancer cells but caused TOPO resistance in the other cells. On the other hand, loading TOPO in 3:15 SO-NE had remarkably improved its’ cytotoxicity in all tested cancer cells. Therefore, TOPO loaded in 3:15 SO-NE is the novel approach in treating cancer. |
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Supervisor |
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Prof. Madeha Nooh Alseeni |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1443 AH
2022 AD |
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Added Date |
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Wednesday, January 25, 2023 |
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Researchers
| هديل محمد بيومي | Bayoumi, Hadeel Mohammed | Researcher | Doctorate | |
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