الفهرس 
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Abstract
B
reast cancer is a complex and heterogeneous disease with respect to pathology, biochemistry and etiology, and is the second leading cause of cancer death. The disease is characterized by the continuous multiplication of the cells in the human body with the inability to be controlled or stopped. Consequently, tumors of malignant cells were formed with the potential to be metastatic. Current medical treatments in breast cancer consist of chemotherapy, radiotherapy, hormonal treatment and targeted therapy, which are sophisticated, expensive and relatively ineffective. Therefore, the development of novel anticancer agents with fewer side effects derived from natural products, especially plants, may provide an alternative and cost-effective treatment modality.
Plants have been demonstrated to be a source of clinically relevant anticancer compounds. For many years herbal medicines have been used and are still used in developing countries as the primary source of medical treatment. Plants have been used in medicine for their natural antiseptic properties. Ulmus pumila, a plant of the genus Ulmus (family Ulmaceae). Ulmus genes having an excellent effect on rheumatoid arthritis, metastasis of cancer and inflammation. The stem and root bark of this species have been used in traditional medicine for edema, mastitis, gastric cancer, and inflammation.
The goal of the current study was to evaluate the chemopreventive effect of Ulmus pumila leaves extract on breast tumorigenesis induced in experimental animals by N-methyl-N-nitrosourea (MNU), in an attempt to inhibit, reverse or restrict the development of breast cancer and inhibit its metastasis and angiogenesis. This target was undertaken through preparing several extracts from the fresh leaves of Ulmus pumila using different solvents (water, methanol, methylene chloride and hexane). Second, the extracts were screened for their cytotoxicity and anti-proliferative activities against MCF-7 breast adenocarcinoma cell line. The most effective extract (Ulmus pumila methanolic extract, UPME) was subsequently used in the in vivo part of the study.
After the determination of UPME safe dose, which represents 1/10 of lethal dose, a total of ninety female Wistar rats divided into six groups; normal control group, UPME-treated group: rats were orally treated daily with (1/10 of the LD50 of UPME, 141.6 mg/kg) for four consecutive weeks, tumor group: breast cancer was induced in female rats by the intraperitoneal (i.p.) injection of two doses of freshly prepared MNU at a dose of 50 mg/kg bw, prophylactic group: rats were orally pretreated daily for four consecutive weeks with 1/10 of the LD50 of UPME before induction of breast cancer, protective group: rats were orally treated daily with 1/10 of the LD50 of UPME starting with the first (i.p.) injection of MNU and continued till the end of the experiment (25 weeks) and therapeutic group: rats were orally treated daily for four consecutive weeks (starting from the age of 25 weeks) with 1/10 of the LD50 of UPME after induction of breast cancer. At the end of the experiment, the activity of liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) and kidney function (creatinine and urea levels), urokinase plasminogen activator concentration (uPA) as a marker of tumor growth, heparanase concentration (HPA) as a marker of metastasis, basic fibroblast growth factor concentration (bFGF) as a marker of angiogenesis, total antioxidant capacity (TAC), B-cell leukemia lymphoma 2 level (Bcl-2) as a marker of apoptosis, cyclooxygenase-2 concentration (COX-2) as a marker of inflammation in serum. Also, histopathological investigations of breast sections were carried out.
Assessment of liver function test (ALT, AST, ALP) and kidney function (creatinine and urea) levels in different groups revealed no significant changes in hepatic enzymes activity and kidney function in the extract treated group, compared to controls. In addition, it was found that the activities of liver enzymes and kidney function were significantly increased in the tumor group, compared to the control group, whereas they were significantly reduced by UPME treatment in the prophylactic, protective and therapeutic groups as compared to the untreated tumor group.
This indicates that the UPME can be safe as well as an effective protective and therapeutic agent for the toxic effects of MNU on liver and kidney functions.
Serum uPA concentration was evaluated, as an indicator for tumor growth, and it was found that it was significantly increased in the tumor group, compared to normal controls. However, it was decreased in the prophylactic, protective and therapeutic groups, compared to the untreated tumor group.
These data show that UPME has an antiproliferative action.
HPA exhibits an essential role in the tumor malignant progression, invasiveness and metastasis. The data of our study revealed that the tumor group had a significantly elevated HPA activity, compared to normal controls. However, HPA activity in the prophylactic, protective and therapeutic groups showed a significant reduction, compared to the untreated tumor group.
These data indicate that UPME can be a powerful natural protector against extracellular matrix degradation and subsequently the tumor invasiveness and metastasis.
bFGF as an effective inducer of the tumor angiogenesis sustaining tumor growth, was also estimated and its concentration was significantly increased in the tumor group, compared to normal controls. On the other hand, the UPME administration in the prophylactic, protective and therapeutic groups improved and significantly reduced bFGF levels, compared to the untreated tumor group.
This demonstrates that UPME is able to perform anti-angiogenic actions through modulating bFGF.
In addition, we had evaluated TAC levels in all various experimental groups. It was found that the TAC level was significantly decreased in tumor group, compared to normal controls. By contrast, UPME administration in the prophylactic, protective and therapeutic groups resulted in a significant enhancement of serum TAC level, compared to the untreated tumor group.
This demonstrates the non-toxic nature of UPME that protects cells against ROS by scavenging free radicals and reducing the expression of stressresponse-related genes.
Also, we had evaluated Bcl-2 level in all experimental groups as it has a pivotal role in the extrinsic apoptotic pathway and limiting tumor cells influence. It was found that Bcl-2 level was significantly increased in the tumor group, compared to normal controls. However, Bcl-2 level was significantly decreased in the prophylactic, protective and therapeutic groups, compared to the untreated tumor group.
These results pointed to that UPME can trigger apoptotic processes.
Moreover, COX-2 as an index for inflammation and participating in immune function, tumor formation or growth and tumor angiogenesis, was assessed and it was shown that COX-2 was significantly increased in the tumor group, compared to normal controls. However, COX-2 concentration was decreased in prophylactic, protective and therapeutic groups, compared to the untreated tumor group.
This shows that UPME has a great effect as an anti-inflammatory and antitumor agent.