title: Cardiac protective effects of dexrazoxane on animal cardiotoxicity model induced by anthracycline combined with trastuzumab is associated with upregulation of calpain-2.
abstract: Cardiotoxicity is a well-recognized side effect induced by chemotherapeutic drugs such as anthracycline and trastuzumab through different mechanisms. Currently, accumulating evidence supports that dexrazoxane (DZR) can minimize the risk of cardiotoxicity. In this study, we investigated whether dexrzoxane could reduce cardiotoxicity in the treatment of anthracycline combined with trastuzumab. We randomly divided 90 experimental F344 rats into control group, chemotherapeutics and trastuzumab (doxorubicin [DOX] + herceptin [Her]) group, and chemotherapeutics, trastuzumab, and DZR (DOX + Her + DZR) group. Animal status and body weight, cardiac function, serum cardiac markers, cardiomyocyte apoptosis of the rats, and expression level of calpain-2 were evaluated. Left ventricular ejection fraction (LVEF) and fractional shortening (FS) of the left ventricle were observed. The serum levels of malondialdehyde (MDA) and cardiac troponin I (cTnI) and cardiomyocyte apoptosis were detected by enzyme linked immunosorbent assay and TdT-mediated dUTP nick end labeling assays. The mRNA and protein level of calpain-2 were measured by reverse transcriptase polymerase chain reaction and Western blot. We observed that the LVEF and FS of the left ventricle were significantly higher in the DOX + Her + DZR group than that in the DOX + Her group (P < 0.05). The serum levels of MDA and cTnI between DOX + Her group and DOX + Her + DZR group were significantly different. In addition, cardiomyocyte apoptosis in the DOX + Her + DZR group was significantly less severe than that in the DOX + Her group (P < 0.05). After DZR treatment, the calpain-2 mRNA and protein levels in the DOX + Her + DZR group were significantly higher than the DOX + Her group (P < 0.05). Our results suggest that DZR can effectively reduce the cardiotoxicity of combinatorial treatment of trastuzumab and anthracycline partly through upregulating calpain-2.
authors: From the 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education; and Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China.
authors: Sheng
authors: S
authors: Zhang
authors: Tingting
authors: T
authors: Meng
authors: Jingjing
authors: J
authors: Liu
authors: Xiaobei
authors: X
authors: Zhang
authors: Jin
authors: J
authors: Zhang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity / Q000517:prevention & control; D064730:Dexrazoxane / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D008315:Malondialdehyde / Q000097:blood; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D011916:Rats, Inbred F344; D013318:Stroke Volume / Q000187:drug effects; D000068878:Trastuzumab; D019210:Troponin I / Q000097:blood; D014463:Ultrasonography; D015854:Up-Regulation
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D012333:RNA, Messenger; D019210:Troponin I; D064730:Dexrazoxane; D008315:Malondialdehyde; D004317:Doxorubicin; D002154:Calpain; C000594975:Capn2 protein, rat; D000068878:Trastuzumab
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