الفهرس 
Introduction and Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Cancer is a large worldwide health problem because of its elevated progression and mortality rate. EAC is a cancer model obtained by transplanting tumor tissues subcutaneously from mouse to mouse. The cancer treatment with one or more cytotoxic anti-neoplastic drugs is called chemotherapy. The current searching for effective nontoxic, inexpensive, and suitable neoadjuvant therapy with Cisplatin (CIS) to improve the effectiveness of CIS and lowering its side effects, in this study we investigated the antitumor effect of Ethoxyquin (EQ) on mice bearing Ehrlich ascites carcinoma (EAC) and checked whether EQ can enhance the anticancer potential of CIS. In this experiment, Mice were divided into eight groups each group have 10 mice were used for assessment of antitumor activity of EQ and 10 mice for evaluation of mean survival time (MST) and increase of life span percentage (% ILS). The groups are group I: (Negative control group) .group II: (EAC- bearing positive control group) .group III: (Cisplatin control group).group IV: (Ethoxyquin control group) .group V: (Ethoxyquin and Cisplatin control group) group VI: (Cisplatin treated group) .group VII: (Ethoxyquin treated group) .group VIII: (Ethoxyquin and Cisplatin treated group) for 3weeks,3 times/ week. Antitumor activity of EQ was monitored by measuring the survival time, counting total number of tumor cells, monitoring the LDHA activity using ELIZA technique, monitoring autophagic activity at the cellular level by flowcytometery, monitoring apoptotic regulated genes (Caspase 3, Bax and Bcl2 genes ) and antioxidant genes (SOD, GSH, and CYTP450) by real time PCR , as well as the biochemical parameters as hepatic enzymes activities in serum , oxidative stress markers in liver homogenate, in addition to complete blood picture (CBC) and histopathological studies of all groups. Combination of Ethoxyquin and Cisplatin enhances the antitumor potential of Cisplatin on EAC cells To assess the anti-tumor effects of EQ against EAC, changes in body weight, count of tumor cells, tumor volume, mean survival time and percentage of life span of treated groups were assessed. The body weight and relative liver weight of non-treated EAC mice increased as compared to normal control mice. To confirm our hypothesis, we treated EAC-bearing mice with EQ and CIS alone and in combination, and examined whether the combined form gives better antitumor potential. Indeed, treatment of EAC mice with EQ and CIS alone or in combination resulted in a decrease in body weight and relative liver weight as compared to non-treated EAC mice. Furthermore, administration of EQ and CIS alone or in combination led to a significant decrease in total, viable, and non-viable tumor cells count as well as tumor volume in comparison with EAC mice. Among the three treatments, EQ plus CIS group showed the lowest body weight, tumor volume, total and viable tumor cells count and the highest non-viable tumor cells count. On the other hand, treatment of mice with EQ and CIS alone or in combination significantly increased ILS and MST as compared to non-treated EAC mice. Effect of Ethoxyquin and/or Cisplatin on haematological and biochemical parameters of EAC bearing mice The current study revealed that treatment with EQ and/or CIS relieved the EAC-induced alteration in some hematological parameters (Hb content, RBCs and WBCs count, and some biochemical parameters (serum activities of AST, ALT, GGT and ALP, as well as total protein and albumin content). In addition, EAC mice treated with EQ alone or combined with CIS showed a significant increase in hepatic antioxidant status (as revealed by elevation of TAC levels, CAT and GST activities) and a remarkable decrease in levels of the lipid peroxidation biomarker and the oxidative stress marker MDA as compared to nontreated EAC mice. Effect of Ethoxyquin and/or Cisplatin on relative expression of apoptotic regulated genes (Bcl2, caspase 3, and Bax) and antioxidant genes (SOD, GSH, and CYTP450) in EAC cells Real time PCR was used to detect the relative expression of apoptotic regulated genes (Bcl2, caspase 3, and Bax) and antioxidant genes (SOD, GSH, and CYTP450). Our results revealed a significant upregulation of caspase3 and Bax genes expression following treatment with EQ and CIS alone and in combination, with highest expression in the combined group, as compared to non-treated EAC group. On the other hand, the same treatments resulted in a significant downregulation of Bcl2, with lowest expression in the combined group, as compared to non-treated EAC group. Results also revealed that treatment with EQ alone or in combination resulted in significant increase in SOD and GSH genes expression as compared with the non-treated EAC group. The same treatment resulted in significant decrease in CytP450 gene expression, as compared with the non-treated EAC group. However, treatment with CIS results in no significance change in SOD, GSH, and CytP450 genes expression. Effect of EQ and/or CIS on lactate dehydrogenae-5 activity In the current study, the non-treated EAC bearing group showed a significant increase in LDH-5 activity in serum and liver tissue, as compared to normal group. Administration of EQ alone or in combination resulted in, in serum as well as in liver tissue, a significant decrease with the lowest reduction in EQ treated group, as compared to non-treated EAC bearing group. Administration of CIS resulted in a significant increase in serum and no significant change in LDH-5 activity in liver tissue as compared to non-treated EAC bearing group. Treatment with CIS and EQ alone or in combination resulted in a significant decrease in LDH-5 activity in EAC cells with the lowest reduction in EQ treated group, as compared to non-treated EAC bearing group. Effect of Ethoxyquin and/or Cisplatin on autophagic activity of EAC cells Our results showed a significant decrease in autophagic activities (as revealed by a reduction in fluorescence intensity of autophagosome marker that determined by flow cytometry) in groups treated with EQ and CIS alone or in combination as compared to nontreated EAC group. However, there was no significant change following treatment with CIS alone. Histopathological findings Histopathological examination revealed normal hepatic architecture with polyhedral hepatocytes with centrally located nuclei. The hepatocytes were arranged in strands alternating with blood sinusoid forming a network around central vein. Kupffer cells were distributed within the blood sinusoids. Liver sections of EAC group displayed distinct disruption of the characteristic cord-like arrangement of the hepatocytes, hepatocytes have clear to foamy cytoplasm with intranuclear cytoplasmic inclusions, sinusoidal infiltration of clumps of Ehrlich tumour cells mixed with lymphocytes. Kupffer cells are increase significantly within the sinusoids. This distorted hepatic structure was partially restored following treatment with EQ and CIS. However, the co-administration of EQ and CIS resulted in nearly complete retrieve to normal liver structure. Conclusion and Recommendation Our study demonstrated that EQ enhances the antitumor potential of CIS against mice bearing Ehrlich ascites carcinoma by inhibition of LDHA enzyme and autophagy, induction of apoptosis, and decreasing the oxidative stress. Thus EQ could be used as a potential neoadjuvant for the antitumor drug CIS. Conclusions and recommendations are that EQ is an autophagic inhibitor, and has apoptotic induction property on tumor cells and lack of toxicity on normal cells increases efficacy of antitumor drug for treating a spectrum of cancers.