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Document Type |
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Thesis |
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Document Title |
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MODULATION OF DOXORUBICIN INDUCED EXPRESSION OF MULTIDRUG RESISTANCE GENE IN BREAST CANCER CELLS BY DILTIAZEM تعديل الجينات المقاومة لعقار الدوكسوروبيسين بواسطة عقار الديلتيازيم في خلايا الثدي البشرية السرطانية |
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Subject |
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Faculty of medicine |
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Document Language |
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Arabic |
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Abstract |
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Doxorubicin (DOX) is an anthracycline antibiotic and one of the most important anticancer agents used in treating breast cancer. Unfortunately, chronic cardiotoxicity and multidrug resistance as well as the development of cardiomyopathy, limit the chemotherapeutic use of DOX. Therefore, this work was directed to evaluate the cytotoxicity of DOX and its capability to arrest, reverse, or delay tumor growth and ameliorate cell resistance by calcium channel blocker (CCB) diltiazem (DIL) in breast cancer MCF-7 cells. The possible protection against DOX induced cardiotoxicity in male Wister rats has also been investigated. To evaluate these effects, we have explored the DOX effects on growth of MCF-7 cells, cell cycle phase distribution, DOX cellular uptake and expression of ABCB1, FOXO3a and p53 genes in the presence and absence of DIL (20 μg /ml). In addition, we studied the ability of DIL to prevent DOX-induced cardiotoxicity after a single injection of DOX (15 mg/kg) in male Wister rats. Addition of DIL in the protocol regimen enhanced the cytotoxic effect of DOX against the growth of MCF-7 cells with IC50 0.21 μg/ml compared to 0.89 μg /ml DOX alone and increased the intracellular level of DOX as well as increased cells accumulation in G2/M phase. This effect was confirmed by the light microscopic study were DIL treatment with DOX showed highly condensed neuclear fragments and rim of cytoplasm were scattered in MCF-7 cells. Moreover, DIL addition to DOX increased down expression of ABCB1gene by more than 4 fold while induced expression of FOXO3a and p53 genes by 1.5 fold compared with DOX alone. On the other hand, DIL treatment showed a protection against DOX-induced cardiotoxicity represented by a decrease in the level of cardiac enzymes CK-MB as well as a decrease in the level of malondialdehyde (MDA) and increased level of total antioxidant capacity (TAC) and glutathione peroxidase (GPx). Histopathological investigation of cardiac cells confirmed the biochemical study, where addition of DIL to DOX showed that the fragmentation of the muscle fiber revealed normal with central vesicular nuclei and prevented a marked disruption of normal cardiac architecture that resulted from DOX treatment. In conclusion, DIL increased the cytotoxic activity of DOX against the growth of MCF-7 cells and reversed the resistant cells to the action of DOX and protect against its cardiotoxicity in the rats. |
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Supervisor |
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Prof. Abdel-Moneim M. Osman |
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Thesis Type |
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Master Thesis |
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Publishing Year |
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1439 AH
2018 AD |
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Co-Supervisor |
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Prof. Zohair A. Damanhori |
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Added Date |
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Tuesday, August 7, 2018 |
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Researchers
| حمدان سالم المالكي | AlMaliki, Hamdan Salem | Researcher | Doctorate | |
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