Alginate Oligosaccharide Prevents Acute Doxorubicin Cardiotoxicity by Suppressing Oxidative Stress and Endoplasmic Reticulum-Mediated Apoptosis.

Jun-Jie Guo,Jian-Bing Zhu,Lei-Lei Ma,Jian Wu,Zhi-Wen Ding,Yi An,Jun-Bo Ge,Yun-Zeng Zou,Hong-Tao Shi

doi:10.3390/md14120231

Abstract

Doxorubicin (DOX) is a highly potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. DOX-induced cardiotoxicity involves increased oxidative stress and activated endoplasmic reticulum-mediated apoptosis. Alginate oligosaccharide (AOS) is a non-immunogenic, non-toxic and biodegradable polymer, with anti-oxidative, anti-inflammatory and anti-endoplasmic reticulum stress properties. The present study examined whether AOS pretreatment could protect against acute DOX cardiotoxicity, and the underlying mechanisms focused on oxidative stress and endoplasmic reticulum-mediated apoptosis. We found that AOS pretreatment markedly increased the survival rate of mice insulted with DOX, improved DOX-induced cardiac dysfunction and attenuated DOX-induced myocardial apoptosis. AOS pretreatment mitigated DOX-induced cardiac oxidative stress, as shown by the decreased expressions of gp91 (phox) and 4-hydroxynonenal (4-HNE). Moreover, AOS pretreatment significantly decreased the expression of Caspase-12, C/EBP homologous protein (CHOP) (markers for endoplasmic reticulum-mediated apoptosis) and Bax (a downstream molecule of CHOP), while up-regulating the expression of anti-apoptotic protein Bcl-2. Taken together, these findings identify AOS as a potent compound that prevents acute DOX cardiotoxicity, at least in part, by suppression of oxidative stress and endoplasmic reticulum-mediated apoptosis.

Highlights

Doxorubicin (DOX), an anthracycline antibiotic, is a widely used and highly potent chemotherapeutic agent to treat a broad range of cancers
We observed whether Alginate oligosaccharide (AOS) treatment (200 mg/kg/day, five days) after DOX injection could exert a protective effect on cardiac dysfunction induced by DOX
Compared with the control (CON) group, mice pre-treated with AOS alone did not exhibit abnormal cardiac function, and there was no difference in left ventricular end-diastolic dimensions (LVEDD) among the four groups (Figure 1B)

Summary

Introduction

Doxorubicin (DOX), an anthracycline antibiotic, is a widely used and highly potent chemotherapeutic agent to treat a broad range of cancers. The mechanisms of DOX-induced cardiotoxicity have not been fully elucidated. Mar. Drugs 2016, 14, 231 been linked to DOX-induced cardiotoxicity [2,3,4]. Anti-oxidative therapies including using antioxidants and transgenic mice overexpressing anti-oxidative enzymes have been verified to be effective in protecting against DOX-induced cardiotoxicity [5,6,7,8]. A recent study has demonstrated that a chemical endoplasmic reticulum chaperone could obliterate DOX-induced cardiac dysfunction [9]. These observations hint that some agents may alleviate DOX-induced cardiotoxicity by inhibiting oxidative stress or endoplasmic reticulum-mediated apoptosis

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Conclusion