الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
5-SUMMARY
Cancer metastasis accounts for approximately 90% of all cancer related deaths. Robust neovascularization and lymphangiogenesis are found in a variety of aggressive malignant tumors and contribute to tumor progression and cancer metastasis (Gomes et al., 2013). Current dietary guidelines to combat chronic diseases including cancer, recommend increased intake of plant foods that are rich in antioxidants, including carotenoids, flavonoids and tanshinones (Mehmet et al., 2012). Apigenin (4, 5, 7 trihydroxyflavone) is a common dietary flavonoid. It has low toxicity, is non mutagenic and is widely distributed in the leaves and stems of dietary tropical vegetables and fruits such as bell pepper, snake gourd and wolfberry leaves Apigenin inhibited tumor angiogenesis which was associated with the decrease of VEGF expression in tumor tissues (Fang et al., 2007). Cryptotanshinone, a natural compound isolated from Salvia miltiorrhiza Bunge (Danshen), has been used in traditional oriental medicine for the treatment of a variety of diseases. It has been also demonstrated that cryptotanshinone has anti-lymphangiogenic activity through the inhibition of STAT3 (Shin et al., 2009).
Therefore, the purpose of this study was to evaluate the ability of apigenin (an antiangiogenic agent) and cryptotanshinone (an antilymphangiogenic agent), either alone or in combination, to inhibit the growth of solid Ehrlich carcinoma (EC) in female mice. The aim of the study was also extended to investigate the probable effect of both compounds to augment the radiosensetivity of tumor cells to gamma radiation and to explore some of the molecular mechanisms involved in these effects.
To achieve this goal, a total of 135 female outbred Swiss albino mice weighing 20-30 g were used and divided into nine groups as follows:
group 1 (Control, C): Mice received a daily intraperitoneal injection of physiological sterile saline-diluted DMSO for 30 consecutive days.
group 2 (E): Mice bearing solid EC inoculated intramuscularly in the right thigh muscle of the lower limb of each mouse.
group 3 (E+AP): Mice bearing solid EC were injected i.p. with 50 mg/kg body weight apigenin for 30 consecutive days starting from the 15th day following EC inoculation.
group 4 (E+CPT): Mice bearing solid EC were injected i.p. with 40 mg/kg body weight cryptotanshinone for 30 consecutive days starting from the 15th day following EC inoculation.
group 5 (E+AP+CPT): Mice bearing solid EC were first injected i.p. with apigenin (50 mg/kg body weight) followed by an i.p. injection of cryptotanshinone (40 mg/kg body weight) 2 h latter for 30 consecutive days starting from the 15th day following EC inoculation.
group 6 (E+R): Mice bearing solid EC were exposed to a single 6.5 Gy whole body γ-irradiation at the 15th day following EC inoculation.
group 7 (E+AP+R): At the 15th day following EC inoculation, mice were first injected i.p. with apigenin (50 mg/kg body weight), followed by a single 6.5 Gy whole body γ-irradiation 30 min latter. Apigenin was administered for 30 consecutive days.
group 8 (E+CPT+R): At the 15th day following EC inoculation, mice were injected i.p. with cryptotanshinone (40 mg/kg body weight), followed by a single 6.5 Gy whole body γ-irradiation 30 min latter. Cryptotanshinone was administered for 30 consecutive days. .
group 9 (E+AP+CPT+R): At the 15th day following EC inoculation, mice were first injected i.p. with apigenin (50 mg/kg body weight), followed by an i.p. injection of cryptotanshinone (40 mg/kg body weight) 2 h latter, and were finally exposed to a single 6.5 Gy whole body γ-irradiation 30 min latter. Apigenin and cryptotanshinone were administered for 30 consecutive days.
The growth rate of solid tumor in all experimental groups was measured by Caliper. At the end of the experiment, whole blood was withdrawn from animals for the analysis of matrix metalloproteinase 2 and 9 activities. Liver was excised for the analysis of oxidative stress biomarkers (MDA and GSH). In addition, the expression of STAT-3, VEGF-C and TNF-α mRNA was measured in solid tumors using RT-PCR. A part of excised tissues (the right thigh muscle and solid EC) was used for estimation of nitric oxide concentration and the level of apoptotic factors (caspase-3 and granzyme-B). In addition, histological examinations were performed to confirm biochemical data.
The results obtained were statistically analyzed and can be summarized as follows:
• Marked reduction in the tumor size, and a radiosensetizing effect was observed in decreasing the tumor size of γ-irradiated-EC-bearing mice coadministered with apigenin, cryptotanshinone or both drugs, respectively with respect to untreated EC-bearing mice.
• Exposure of EC-bearing mice to γ-irradiation either alone or along with apigenin or cryptotanshinone treatment produced a significant downregulation in the expression of tumor STAT3, VEGF-C and TNF-α gene. where the three treatment modalities caused the most pronounced downregulation in the expression of these genes compared to untreated EC-bearing mice.
• Whole body γ-irradiation of EC-bearing mice either alone or along with apigenin or cryptotanshinone treatments produced a significant decrease in the activity of MMP-2 and -9 with respect to untreated EC-bearing mice.
• Treatment of EC-bearing mice with apigenin, cryptotanshinone or both compounds, either alone or in combination with γ-irradiation resulted in a significant suppression of tumor nitric oxide level which is associated with sharp increase in caspase-3 and granzyme-B levels, compared to untreated EC-bearing mice.
• Treatment with apigenin and/or cryptotanshinone of EC-bearing mice and those irradiated neutralized the changes induced in hepatic redox status, is demonstrated by reducing LPO and increasing hepatic glutathione, with respect to untreated EC-bearing mice.
Concomitant with the improvement of biochemical markers, the histological finding in tissues (right thigh muscle and solid EC) showed an ameliorative effect of AP and CPT.
According to the obtained results it could be concluded that Ap and CPT may be used as potential therapeutic agents for cancer for reducing tumor neovascularisation in order to suppress tumor growth and metastasis via enhancing the sensitivity of tumor cells to ionizing radiation in addition to the protection of normal cells against harmful effects of radiation and chemotherapeutic toxicity.