Abstract
Doxorubicin (adriamycin), an anthracycline antibiotic, is commonly used to treat many types of solid and hematological malignancies. Unfortunately, clinical usage of doxorubicin is limited due to the associated acute and chronic cardiotoxicity. Previous studies demonstrated that Astragalus polysaccharide (APS), the extracts of Astragalus membranaceus, had strong anti-tumor activities and anti-inflammatory effects. However, whether APS could mitigate chemotherapy-induced cardiotoxicity is unclear thus far. We used a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model to explore the function of APS. GFP-LC3 adenovirus-mediated autophagic vesicle assays, GFP and RFP tandemly tagged LC3 (tfLC3) assays and Western blot analyses were performed to analyze the cell function and cell signaling changes following APS treatment in cardiomyocytes. First, doxorubicin treatment led to C57BL/6J mouse heart failure and increased cardiomyocyte apoptosis, with a disturbed cell autophagic flux. Second, APS restored autophagy in doxorubicin-treated primary neonatal rat ventricular myocytes and in the doxorubicin-induced heart failure mouse model. Third, APS attenuated doxorubicin-induced heart injury by regulating the AMPK/mTOR pathway. The mTOR inhibitor rapamycin significantly abrogated the protective effect of APS. These results suggest that doxorubicin could induce heart failure by disturbing cardiomyocyte autophagic flux, which may cause excessive cell apoptosis. APS could restore normal autophagic flux, ameliorating doxorubicin-induced cardiotoxicity by regulating the AMPK/mTOR pathway.
Highlights
Doxorubicin (DOX) is widely used as a broadspectrum anticancer chemotherapeutic drug
Our results revealed that Astragalus polysaccharide (APS) could restore normal autophagic flux and improve heart function by regulating AMP-activated protein kinase mammalian target of rapamycin (mTOR) (AMPK)/mTOR pathway in doxorubicin-induced cardiotoxicity
The cell viability decline might result from autophagy more than apoptosis in the treatment of 0.5μM doxorubicin
Summary
Doxorubicin (DOX) is widely used as a broadspectrum anticancer chemotherapeutic drug Treatment with this drug results in generation of reaction oxygen species (ROS), DNA mutagenesis, inhibition of protein synthesis, cell membrane damage, and cell apoptosis [1]. Elucidating the mechanism underlying DOX-induced cardiotoxicity may identify strategies to reduce cardiomyopathy risks for cancer patients. Previous studies suggested that free radical-induced mitochondrial damage due to elevated ROS production is the major contributing factor to doxorubicin-induced cardiotoxicity, but recent reports have demonstrated www.impactjournals.com/oncotarget that ROS scavengers failed to prevent heart failure [5, 6]. Recent evidence suggests that dysregulation of autophagy may contribute to cardiomyocyte loss, causing heart failure [9]
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