الفهرس 
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Abstract
The present study was planned to evaluate the effect of Withania somnifera extract / Gadolinium III oxide nanocomposite (WSGNC) as radiosensitizer and anticancer in tumour model of animals which leads to reduce the treatment dose of radiation during radiotherapy.
Cell viability was assayed in vitro and in vivo studies, tumour size and weight were also determined. DNA fragmentation, caspase-3 activity, mitochondrial enzymes activities, NADH-ubiquinone oxidodreductase (complex I), NADH-cytochrome c oxidoreductase (Complex II) and succinate-cytochrome c oxidoreductase (Complex III) were determined in cancer tissues. In addition oxidative stress was assayed by measuring the content of malondialdehyde (MDA) as a marker of lipid peroxidation. Glutathione content (GSH) as well as superoxide dismutase (SOD) and catalase activities were determined as markers of the antioxidant status.
The present study was carried out on 190 female albino mice body weight 22-25g and solid tumours were produced in 130 mice by intramuscular inoculation with 0.2 ml of EAC, which contained 2.5 x 106 viable EAC cells, in the right thigh of the lower limb of each mouse. Mice with a palpable solid tumour diameter (10mm³) that developed within 10 days after inoculation were used in the study.
Experimentl I:
In the present study animals were divided into seven main groups, each group contains 10 mice:
group I: Animals bearing tumour left without any treatment.
group II: Animals bearing tumour were exposed to 3 doses of
radiation (2 Gy / dose) weekly for 3 weeks.
group III: Animals bearing tumour were injected i.p with
(WSGNC) (3 times / week) in a dose of 227 mg/kg b.w then exposed to 3 doses of radiation (2 Gy / dose) weekly for 3 weeks.
group IV: Animals bearing tumour were exposed to 3 doses of
radiation (4 Gy / dose) weekly for 3 weeks.
group V: Animals bearing tumour were injected i.p with
(WSGNC) (3 times / week) in a dose of 227 mg/kg b.w then exposed to 3 doses of radiation (4 Gy / dose) weekly for 3 weeks.
group VI: Animals bearing tumour were exposed to 3 doses of
radiation (6 Gy / dose) weekly for 3 weeks.
group VII: Animals bearing tumour were injected i.p with
(WSGNC) (3 times / week) in a dose of 227 mg/kg b.w then exposed to 3 doses of radiation (6 Gy / dose) weekly for 3 weeks.
from the previous irradiated groups a single dose of γ- irradiation was selected to apply in animals bearing tumour.
Experimentl II:
In the present study animals were divided into eight main groups, each group contains 15 mice:
group I: Control group left without any treatment.
group II: Animals were exposed to 6 Gy fractionated, applied in 3 doses of 2 Gy /week for 3 weeks.
group III: Animals were injected i.p with (WSGNC) (3 times / week) in a dose of 227 mg/kg b.w for 3 weeks.
group IV: Animals were injected i.p with (WSGNC) (3 times / week) in a dose of 227 mg/kg b.w then exposed to 6 Gy fractionated, applied in 3 doses of 2 Gy / week for 3 weeks.
group V: Animals bearing tumour left without any treatment.
group VI: Animals bearing tumour were exposed to 6 Gy fractionated, applied in 3 doses of 2 Gy / week for
3 weeks.
group VII: Animals bearing tumour were injected i.p with (WSGNC) (3 times / week) in a dose of 227 mg/kg b.w for 3 weeks.
group VIII: Animals bearing tumour were injected i.p with (WSGNC) (3 times / week) in a dose of 227 mg/kg b.w then exposed to 6 Gy fractionated, applied in 3 doses of 2 Gy/week for 3 weeks.
The results revealed that treatment of Erlich Ascites Carcinoma (EAC) cells with (WSGNC) represented a higly significantly decrease in viability of the cells at different concentrations as compared to EAC.
Treatment of Solid Ehrlich Carcinoma bearing mice with WSGNC combined with γ-radiation led to a significant decrease in the tumour size and weight, mitochondrial enzyme activities and SOD activity, on the other hand, a significant increase was observed in DNA fragmentation, caspase-3 activity while a non-significant change was recorded in GSH content, MDA concentration and CAT activity in cancer tissues.
A significant increase in tumour volume and tumour weight of animals bearing tumour was observed. The increase in tumour weight may be due to accumulation of peritoneal fluid in tumour-induced mice. Treatment with (WSGNC) combined with low dose of radiation reduced the tumour volume and tumour weight and hence increased the life span.
The mitochondria electron transport complexes (1-V) are the key molecular machineries that execute the biochemical processes of mitochondria respiration and ATP synthesis Withaferin A -induced apoptosis is mediated by reactive oxygen species (ROS) production due to inhibition of mitochondrial respiration. Enhanced ROS generation induces dissociation of the I-III supercomplex with consequence lack of efficient electron channeling from complex I to complex III; moreover the concomitant disruption of complex I assembly induced by supercomplex dissociation might also account for the decrease of NAD-linked respiration and ATP synthesis.
Withaferin A induces apoptosis associated with (i) mitochondrial instability-mediated apoptotic signaling orchestrated by a time-dependent down regulation of the anti-apoptotic protein (Bcl-2)/Bax ratio, (ii) release of cytochrome c from mitochondria, (iii) activation of caspases (9 and 3) and (iv) subsequently accumulation of cells in the sub-G0 phase followed by DNA fragmentation.
A number of mechanisms are involved in radiosenstization some of the commonly reported mechanisms include: enhanced generation of ROS/RNS, selective depletion of tumour cell antioxidants and antioxidant enzymes, increased of lipid peroxidation, depletion of GSH, elevated levels of lipid peroxidation and DNA damage of tumour cells, formation of DNA adducts, inhibition of DNA repair, inhibition of DNA synthesis, induction of cell cycle arrest, induction of apoptosis and depletion of protein kinase c.
The results also revealed that treatment of Solid Ehrlich Carcinoma bearing mice with (WSGNC) alone or combined with low dose of radiation ameliorated the biochemical disturbances appeared in the liver parameters under investigation.
It is concluded that WSGNC can be considered as a radio-sensitizer and anticancer modulator, suggesting its possible role in reducing the radiation exposure dose during radiotherapy.