Rong Wu1, Hui-Lin Wang1, Hai-Lun Yu2, Xiao-Hua Cui1, Meng-Ting Xu1, Xu Xu2, Jian-Ping Gao3. 1. Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. 2. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. 3. Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: zydgjp@aliyun.com.
Abstract
BACKGROUND: Doxorubicin (DOX) is an antitumor antibiotics used against malignancies. But its toxicity limits the therapy of DOX. OBJECTIVE: The purpose of this study was to evaluate DOX toxicity and the alteration of energy metabolism after short term and long term treatment. METHODS: Male Sprague-Dawley rats were randomly assigned to four groups: Short term control group, short term DOX treatment group, long term control group and long term DOX treatment group. In short term treated group, rats were injected with DOX i.p. at a dose of 2.5 mg/kg every 48 h for six equal injections. In long term, treated group, rats were tail-intravenously injected with DOX at a dose of 3 mg/kg once a week for four weeks. At the end of the experiment, histopathological changes, general blood biomarkers, endogenous antioxidant enzymes, cardiac energy metabolism and related mRNA expression of AMPK signal pathway were determined. RESULTS: DOX induced prominent oxidative stress, a higher mortality rate, histological and ECG changes, obvious cardiac hypertrophy, acute cardiac damage and cardiac energy impairment in short term treatment rats. In long term treatment rats, DOX caused serious nephropathy and systolic dysfunction, terrible cardiac energy impairment, clear alteration of substrate utilization and AMPK signal pathway. CONCLUSION: DOX treatment can induce different damages after short term and long term treatment. In short term treatment group, rats experienced a terrible mortality rate about 40%, the acute cardiac damage, cardiac energy impairment and an early heart failure which are potential connected with reduction of glucose utilization. In the long term treatment group, serious nephropathy and obvious changes of mRNA expressions of AMPK signal pathway were observed. Meanwhile, the serious cardiac energy impairment and substrate utilization alteration denote an obviously heart failure. This study could be helpful to develop therapy strategies of DOX complications for clinical application.
BACKGROUND:Doxorubicin (DOX) is an antitumor antibiotics used against malignancies. But its toxicity limits the therapy of DOX. OBJECTIVE: The purpose of this study was to evaluate DOXtoxicity and the alteration of energy metabolism after short term and long term treatment. METHODS: Male Sprague-Dawley rats were randomly assigned to four groups: Short term control group, short term DOX treatment group, long term control group and long term DOX treatment group. In short term treated group, rats were injected with DOX i.p. at a dose of 2.5 mg/kg every 48 h for six equal injections. In long term, treated group, rats were tail-intravenously injected with DOX at a dose of 3 mg/kg once a week for four weeks. At the end of the experiment, histopathological changes, general blood biomarkers, endogenous antioxidant enzymes, cardiac energy metabolism and related mRNA expression of AMPK signal pathway were determined. RESULTS:DOX induced prominent oxidative stress, a higher mortality rate, histological and ECG changes, obvious cardiac hypertrophy, acute cardiac damage and cardiac energy impairment in short term treatment rats. In long term treatment rats, DOX caused serious nephropathy and systolic dysfunction, terrible cardiac energy impairment, clear alteration of substrate utilization and AMPK signal pathway. CONCLUSION:DOX treatment can induce different damages after short term and long term treatment. In short term treatment group, rats experienced a terrible mortality rate about 40%, the acute cardiac damage, cardiac energy impairment and an early heart failure which are potential connected with reduction of glucose utilization. In the long term treatment group, serious nephropathy and obvious changes of mRNA expressions of AMPK signal pathway were observed. Meanwhile, the serious cardiac energy impairment and substrate utilization alteration denote an obviously heart failure. This study could be helpful to develop therapy strategies of DOX complications for clinical application.
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Authors: Mária Lódi; Dániel Priksz; Gábor Áron Fülöp; Beáta Bódi; Alexandra Gyöngyösi; Lilla Nagy; Árpád Kovács; Attila Béla Kertész; Judit Kocsis; István Édes; Zoltán Csanádi; István Czuriga; Zoltán Kisvárday; Béla Juhász; István Lekli; Péter Bai; Attila Tóth; Zoltán Papp; Dániel Czuriga Journal: J Transl Med Date: 2019-07-19 Impact factor: 5.531
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