The Study Of Low Dose Radiation Enhances The Effect Of Doxorubicin-induced Anti-tumor And Reduces Its Cardiotoxicity Via MTOR Signaling Pathways

Background and purpose: Doxorubicin(DOX)as a commonly used anthracycline anti-tumor drugs,in the anti-tumor at the same time,the normal tissues were also damaged and its cardiotoxicity was particularly evident.How to reduce DOX-induced cardiotoxicity without compromising its anti-tumor effect is a difficult problem facing clinical practice.Studies have shown that low dose radiation(LDR)can stimulate the normal tissue of the excitatory effect and adaptive response,LDR also has a certain anti-tumor effect.Some scholars have confirmed that m TOR(mammalian target of rapamycin)signaling pathways is not only involved in the proliferation and apoptosis of tumor cells,but also plays an important role in the growth and metabolism of cardiomyocytes.Another study found that LDR can promote the growth and development of normal tissue by regulating the upstream of the m TOR signaling pathways,and how LDR impacts the tumor tissue and myocardial tissue through m TOR signaling pathways,at home and abroad has not been reported yet.In our previous study,we found that pre-LDR could rescue the cardiotoxicity by alleviating oxidative stress and reducing mitochondrial damage DOX-induced,and found that LDR combined with DOX had some synergistic anti-tumor effect on tumor tissue growth.In view of the highest incidence of female tumor,the breast cancer was chosen as the research object in this study.We establish the subcutaneous transplanted tumor model of breast cancer BALB/c mice,by observing the weight of tumor-bearing mice and transplanted tumor,studying the proliferation and angiogenesis and apoptosis of transplanted tumor cells,detecting and analyzing theexpression of m TOR signaling pathways protein and apoptosis-related protein in both transplanted tumor tissue and myocardium,to explore the effect of LDR on anti-tumor effect and myocardial injury induced by DOX and its possible mechanism.Materials and methods: Twenty-four BALB/c healthy female mice(8 week-old)were selected.Each mouse was injected right-armpit with serum-free 4T1 breast cancer cell suspension 0.1 ml(2x107/ml)to construct breast cancer BALB/c mice subcutaneous transplanted tumor model.When tumor diameter for 3-5 mm,the tumor-burdened rats were randomly divided into four experimental groups: Control group,LDR group(75 m Gy),DOX group(intraperitoneal injection of DOX),LDR+DOX group(LDR 72 hours later intraperitoneal injection of DOX).We observe how LDR and DOX affect the rat weight and tumor weight by weighing the tumor-bearing rat weight and tumor weight.The expression levels of Ki-67 and CD34 were detected by immunohistochemical method,so as to measure the cell proliferation and angiogenesis of tumor;HE staining and TUNEL method to detect the tumor cell apoptosis;Western Blot method to analysis the apoptosis-related proteins and m TOR signaling pathways protein expression in the experimental tumor tissue and the myocardial tissue.Results: Tumor-burdened rat weight results: DOX and LDR+DOX group weight decreased,DOX group decreased significantly.Tumor weight results: DOX group and LDR+DOX group decreased,LDR+DOX group decreased significantly.HE staining results: tumor tissue nests necrosis in DOX group;LDR+DOX group flaky necrosis.TUNEL test results: green fluorescent area increased both in DOX group and LDR+DOX group of tumor tissue and was significantly in LDR+DOX group.Immunohistochemical results: both Ki67 and CD34 positive staining rate in DOX group and LDR+DOX group of tumor tissue decreased and was significantly in LDR+DOX group.Western Blot results: Tumor tissue: The expression of Bcl-2 in LDR+DOX group was significantly lower than that in DOX group;The expression of both Bax and Caspase3 in DOX group and LDR+DOX group increased,Caspase3 increased significantly in LDR+DOX group;Compared to the DOX group,the expression of m TOR,EIF4 E and 4EBP1 in LDR+DOX group decreased.Myocardial tissue: The expression of Bcl-2 in DOX group was down-regulated,was up-regulated in LDR+DOX group;both Bax and Caspase3 was up-regulated in DOX group,was down-regulated in LDR+DOX group.The expression of m TOR,EIF4 E and 4EBP1 in DOX group was down-regulated,the expression of m TOR and EIF4 E in LDR+DOX group was up-regulated,while 4EBP1 was down-regulated.Conclusion: LDR could enhance the anti-tumor effect and mitigate cardiotoxicity induced by DOX.The mechanism may be that LDR could regulate the m TOR signaling pathways of transplanted tumor tissue,blocking tumor cell proliferation and angiogenesis,accelerating tumor cell apoptosis and therefore enhance DOX-induced tumor-inhibition effect.LDR could affect the expression of apoptosis-related gene protein expression by regulating m TOR signaling pathways in myocardial tissue so as to reduce myocardial cell apoptosis and cardiotoxicity induced by DOX.LDR is expected to become an auxiliary means in the clinical treatment of tumor.