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

Posted by:bozhihuili    Published:2017-01-16 14:06

Alginate Oligosaccharide Prevents Acute Doxorubicin Cardiotoxicity by Suppressing Oxidative 

Stress and Endoplasmic Reticulum-Mediated Apoptosis


, , and

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, 

Fudan University, 180 Feng Lin Road, Shanghai 200032, China

Department of Cardiology, The Affiliated Hospital of Qingdao University, 16 Jiang Su Road, 

Qingdao 266003, China

Academic Editor: Peer B. Jacobson

Received: 11 September 2016 / Revised: 7 December 2016 / Accepted: 9 December 2016 / 

Published: 20 December 2016


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 


Keywords: alginate oligosaccharide; doxorubicin cardiotoxicity; oxidative stress; endoplasmic 

reticulum; apoptosis


4. Materials and Methods

4.1. Preparation of AOS

AOS, a gift from Qingdao BZ Oligo Biotech Co. Ltd (Qingdao, China), was produced by the

method of enzymatic degradation as previously described [43]. Briefly, alginate (5 g) derived from

Laminaria japonicawith an M/G ratio of 1.86/1 [44] was dissolved in 500 mL of 50 mmol/L Tris-HCL

buffer (pH 7.0), which was added to 200 units of alginate lyase purified fromPseudomonassp. HZJ

216. The enzymatic reaction was performed at 30C for 6 h, and then terminated by boiling in water

for 5 min. The AOS was initially separated by adjusting the pH of the supernatant to 2.85. Next, the

methods of anion-exchange chromatography and desalting were used to further purify the AOS. 

Then,the methods of High Performance Gel Permeation Chromatography (HPGPC) (Dionex, 

Sunnyvale,CA, USA) and Electrospray Ionization Mass Spectroscopy (ESI-MS) (Agilent 

Technologies, Santa Clara,CA, USA) were used to determine the relative molecular mass and 

degree of polymerization (DP) of the AOS. The relative molecular weight of AOS is approximately 

1.2 kDa (Figure S1), and the DP of AOS mainly ranges from 2 to 6 (Figures S2 and S3, Tables 

S1 and S2). Lastly, the 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy method was 

performed to determine the M/G ratio of AOS which is 1/2.6 (Figure S4). The chemical structure 

of AOS acquired through enzymatic degeneration was shown in Figure7.


Figure   7.   Schematic  representation   of   the   molecular  structure   of   alginate   oligosaccharide   

(AOS)  prepared  by  enzymatic   degradation.

5. Conclusions
The current study is the first to demonstrate that AOS successfully prevents acute DOX 

cardiotoxicity in mice, at least in part, by suppression of oxidative stress and endoplasmic

reticulum-mediated apoptosis. Our data indicate that AOS may clinically serve as a novel 

preventive strategy against acute DOX cardiotoxicity. However, we should not ignore the 

question of whether AOS administration interferes with the anticancer activity of DOX, which 

was not illuminated in the present study. Moreover, the pharmacokinetics of AOS were also 

not investigated. The challenge for future studies is to focus on answering these important 


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