الفهرس 
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Abstract
The present work aimed to study the antitumor efficacy of Curcumin-Zinc Oxide Nano Particles (Cur-ZnONPs) synthesized bya Ball Mail Technique.
The antitumor efficacy of (Cur-ZnONPs) was studied in vitro against human breast carcinoma cell line (MCF-7) and in vivo against 7, 12 Dimethyl benz[a]anthracene (DMBA)-induced mammary gland carcinogenesis of female Swiss albino rat model.
The biosynthesized Curcumin-Zinc Oxide Nano Particles (Cur-ZnONPs) were characterized by using dynamic light scattering (DLS) , Transmission electron microscope (TEM), the results revealed that Cur-ZnONPs were of spherical shape with relatively narrow particle size distribution and size ranging from 91.28-141.8 nm. The UV/VIS scan showed 2 narrow peaks at wave lengths 345 and 490 nm.
In vitro study of Cur-ZnONPs on human breast carcer cell line (MCF-7) showed toxicity with IC50 of 122 ± 4.1 μg/ml. while the in vivo study, a narrow scale experiment was performed to determine the LD50 of Cur-ZnONPs which was found to be 4 mg/kg b. w. and the safe dose was calculated by dividing LD50 by 10 to be used as a safe dose in the in vivo study. Forty female Swiss albino rats weighing (120±20 gm) were equally divided randomly into the following 4 groups:
group I (control healthy group): rats were received 1.0 ml of physiological saline solution/day orally.
group II (DMBA- induced mammary gland carcinogenesis group): rats were received a single dose of 20.0 mg of DMBA/kg b. w. dissolved in 1.0 ml of olive oil by oral gastric intubation then animals were palpated weekly to monitor changes in the mammary glands.
group III (Cur-ZnONPs group): at the 7th month, rats were received a daily oral dose of 0.4 mg of Cur-ZnONPs /kg b.w. by gastric intubation for one month.
group IV (DMBA+Cur-ZnONPs): rats were received a single dose of 20.0 mg of DMBA/kg b. w. dissolved in 1.0 ml of olive oil by oral gastric intubation 7 months earlier for cancer induction then they were received a daily oral dose of 0.4 mg of Cur-ZnONPs /kg b.w. by gastric intubation for one month.
At the end of the experiment (after 8 months), rats were anesthetized and sacrificed, blood samples were obtained via heart puncture and mammary glands were excised for evaluation of several biochemical and molecular parameters in addition to the histopathological study.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured as markers for liver function; serum urea and creatinine were measured as markers for kidney function. In addition to evaluation of the value of total iron binding capacity (TIBC) . Also, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, reduced glutathione (GSH) content and protein intensity of phosphatidylinositide 3-kinases (PI3K) and protein kinase B (AKT) were measured in 10% mammary gland tissue homogenates.
The obtained results of the current work revealed that administration of DMBA resulted in significant elevations of ALT and AST activities as well as urea and creatinine levels in an indicating manner of occurrence of damage to those internal organs (liver and kidney) which could be due to the produced reactive oxygen species by DMBA which also was manifested clearly in significant increasing of MDA content and significant decreasing of the activity of SOD and GSH content. Also a significant increase in the concentration of caspase-3 was noted indicating the induction of apoptosis by DMBA. In the same time, DMBA administration resulted in a significant overexpression of both of AKT &PI3K protein intensity indicating the staking of PI3K/ Akt signaling pathway in “on” position which resulting in cellular surviving.
Furthermore, significant increasing of TIBC was noted indicating the ability of malignant cell to uptake much more iron which was in line with their far greater requirement for iron for proliferation .
Also histopathological alterations in the architecture of the mammary glands were appeared clear in proliferative hyperplasia of the lining epithelial cells of the acini and lactiferous ducts with cystic dilatation as well as stratification.
Treatment of the induced mammary gland carcinogensis with Cur-ZnONPs resulted in amelioration of the investigated biochemical parameters which was manifested clearly in significant decreasing of the activities of ALT&AST, levels of urea and creatinine indicating the reflection of the damage action induced by DMBA. Also, improving of antioxidant state occured by increasing SOD activity and GSH content and decreasing of oxidative stress state by depletion of lipid peroxidation marker (MDA content).
Treatment with Cur-ZnONPs also induced the apoptotic process by increasing caspase-3 concentration and decreasing of AKT &PI3K protein intensity indicating the down regulation of AKT &PI3K signaling pathway.
A mild recurrence of normal mammary gland tissue was histopathologically appeared by treating of Cur-ZnONPs as there wasno hyperplastic changes were noted, only a mild stratification of the acinar lining epithelium was found.
from the aforementioned results of the current work, Cur-ZnONPs could be a promising additional agent with the conventional breast cancer therapies which may tackle their the limitations and overcome the resistence of the malignant cells to those conventional therapeutis strategies.