الفهرس 
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Abstract
Breast cancer is a common cause of death in the women worldwide in spite of the advanced treatment options. Since the incidence of breast cancer increases dramatically all over the world, searching for effective treatment is crucial. Chemotherapeutic agents are the most commonly used but they can cause serious systemic side effects, which limits their use. In addition, tumor drug resistance is the most frequent cause of treatment failure and disease progression. Consequently, this requires a paradigm shift in the mode of treatment strategies for cancer. Imatinib mesylate is a tyrosine kinase inhibitor, which commonly used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. It blocks the tyrosine kinase activity of BCR-Abl, PDGFRs and KIT4 proteins. Multidrug resistance protein -1 or p-glycoprotein-1 is an important protein of the cell membrane that pumps many foreign substances out of cell. Overexpression of the breast cancer resistance protein (ABCG2) and MDR-1 confer resistance to imatinib in CML. Hesperidin is a natural product belongs to flavanones class of flavonoids and is known to possess broad-spectrum applicability to prevent dreadful diseases such as cardiovascular disease, neurodegeneration, and cancer. The reported anticancer effects of hesperidin have been found to be associated with its anti-oxidant and anti-inflammatory activities and it is considered as P-gp inhibitor. Dipyridamole, a traditional anti-platelet agent, is an inhibitor of PDE3 and PDE5 and inhibit the re-uptake of adenosine. Previous studies have reported that dipyridamole enhanced the cytotoxicity of many anti-tumor drugs as well as prevented tumor progression and decreased the proliferative activity of cancer cells. It could enhance cellular sensitivity to a variety of anticancer agents by its inhibitory effect on P-gp. Cancer nanotechnology has been extremely evaluated and implemented in cancer management and therapeutics that minimizes off-target toxicity of many cancer drugs including imatinib mesylate. Also, this can minimize the cytotoxicity of the drug to normal cells. This study aimed to evaluate the potential enhancement of anticancer effect of imatinib by either dipyridamole or hesperidin in SEC model in mice. Also, to clarify the possible mechanism(s) through which dipyridamole and hesperidin may produce their potential beneficial effects in cancer chemotherapy. To achieve these objectives, a model of SEC was induced in female Swiss albino mice by injecting 0.2 ml viable EAC cells (5x106) subcutaneously into the back of mice and left for 10-12 days. The treatment course was started on day 12 after implantation of EAC cells for 16 days on the basis of daily injections. At the end of the treatment period (day 28), blood was withdrawn by exsanguinations through jugular vein puncture into heparinized tubes for: • Determination of hemoglobin content (Hb), red blood cells count (RBCs), white blood cells count (WBCs) and platelets count. Serum was collected and stored at -20°C as aliquot for biochemical determination of: • Alanine aminotransferase activity. • Aspartate aminotransferase activity. • Lactate dehydrogenase activity. • Alkaline phosphatase activity. solid tumor was excised and weighted, then divided into two portions, the first portion was washed with saline, stored at liquid nitrogen and kept frozen at -80°C for determination of the following parameters: • Vascular endothelial growth factor content. • Caspase-3 content. • Ki-67 content. • Mdr-1 gene expression. The second portion of the solid tumor was fixed in 10% neutral buffered formalin (pH 7.4) for: • Histopathological examination by hematoxylin and eosin (H&E) staining. • Immunohistochemical detection of Bcl-2 and Bax activity for assessment of apoptosis. The heart was also removed and washed with saline and fixed in 10% neutral buffered formalin for histopathological examination by H&E staining. The time-course effects of different treatments on the volume of SEC were also assessed. Treatment of SEC-bearing mice with IM50 (50 mg/kg) or IM100 (100 mg/kg) for 16 days resulted in the following changes in the assessed parameters compared to SEC control group: • Significant reductions in the tumor volume and the weight. • Significant reduction in VEGF and Ki-67 contents. • Significant increase in caspase-3 content. • Significant increase in mdr-1 gene expression. • Significant reduction in hemoglobin content, RBCs, WBCs and platelets count. • Significant increase in serum AST, ALT, LDH and ALP activity. • Histopathological examination of SEC sections showed neoplastic mass that displays moderate necrosis of neoplastic cells. • Histopathological examination of cardiac sections showed vacuolation of cardiomyocytes and hemorrhage in myocardium for IM50 and fibroblastic proliferation with deposition of collagenous stroma replacing necrotic cardiomyocytes in myocardium with IM100. • Immunohistochemical staining revealed (+ ve) mild positive immunostain with IM50 and (++ ve) moderate positive with IM100 for Bax and (++ ve) moderate positive immunostain with IM50 and (+ ve) mild positive immunostain with IM100 for Bcl-2.