Low-Dose Radiation Enhanced Inhibition of Breast Tumor Xenograft and Reduced Myocardial Injury Induced by Doxorubicin

Abstract

We reported that low-dose radiation (LDR) alleviated cardiotoxicity of doxorubicin (DOX) via inhibiting myocardial cell apoptosis and oxidative stress in vivo. Here, we tested whether LDR could enhance chemotherapeutic effect of DOX and alleviate myocardial injury induced by DOX by observing cell proliferation, apoptosis, and metastasis of heterotopic tumor in vivo. Mice implanted with 4T1 breast carcinoma cells were given 7.5 mg/kg DOX or 0.9% NaCl solution 72 hours after LDR (0 or 75 mGy). The histology of tumor tissue was observed by hematoxylin and eosin staining, the apoptosis was determined by terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling, and the expression of Ki67, Bcl-2, Bax, cleaved caspase3, matrix metalloproteinase 2 (MMP2), MMP9, and CD34 was detected by Western blot. Expression of Ki67 and CD34 was also detected by immunohistochemistry. Results showed that cell proliferation of the breast tumor and protein expression of the metastasis-related molecules were significantly reduced and the apoptosis of tumor cells was significantly increased in the LDR + DOX-treated tumor-bearing mice. Pretreatment with LDR significantly prevented DOX-induced cardiotoxicity likely through preventing DOX-induced mitochondrial Bcl2/Bax dyshomeostasis-induced caspase-3 cleavage-dependent apoptosis. These results suggested that LDR not only enhances DOX antitumor effect but also reduces DOX cardiotoxicity, which may potentially overcome the limitation for DOX clinical usage.