Abstract
We previously reported that Vitamin C (Vit C) protects against doxorubicin (Dox)-induced cardiotoxicity by reducing oxidative stress, p38 mitogen-activated kinase (MAPK) and p53 activation and rescuing cell death in isolated adult cardiomyocytes. The pattern of activation and the role of oxidative stress as well as down-stream mechanisms for such protection remain elusive. Therefore the present study aims to analyze time-dependant generation of reactive oxygen species (ROS) and the activation of stress induced signalling pathways in cardiomyocytes treated with Dox and Vit C. The data provides further understanding of heart pathophysiology in response to Dox at the cellular level, and may help to optimize the timing of various therapeutic approaches. Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to Dox (10 μM), Vit C (25 μM), and Dox + Vit C for different time intervals up to 24 h. p38-JNK (SB203580) and p53 (pifithrin-α) inhibitors were used to determine the role of each respective signalling protein. Dox administration to cardiomyocytes increased the levels of ROS in a time-dependent manner that followed the activation of stress-induced proteins p53, p38 and JNK MAPKs, culminating in an increase in autophagy and apoptosis markers. Dox-induced increase in ROS was alleviated by Vit C adjuvant treatment at all time-points and this was also correlated with blunting of the activation of the studied signaling pathways leading to the prevention of apoptosis and preservation of cell viability. Protective effect of Vit C against the activation of stress induced proteins, autophagy and apoptosis was mainly attributed to its antioxidant properties even though blockage of p38, JNK and p53 by pharmacological inhibitors also suppressed Dox-induced apoptosis. ROS is defined as a key inducer of cardiomyocyte damage under Dox exposure; Vit C could effectively counteract all Dox-induced changes in cardiomyocytes and may potentially be used as an antioxidant adjuvant therapy to protect against Dox-induced cardiomyopathy.
Highlights
The two leading causes of death worldwide, cardiovascular diseases and cancer [1,2], can be closely related considering that cancer survivors are at higher risk to develop heart failure due to the type of chemotherapy used [3]
Cardiomyocyte viability was assessed after 48h of Dox treatment, the number of viable cells obtained after this exposure time was below 50%
The reliability of data obtained in cultured adult cardiomyocytes is highly dependent on preservation of the original phenotype which can change after a prolonged culture as well as exposure time [23]
Summary
The two leading causes of death worldwide, cardiovascular diseases and cancer [1,2], can be closely related considering that cancer survivors are at higher risk to develop heart failure due to the type of chemotherapy used [3]. The use of anticancer drug Doxorubicin (Dox) in cancer patients has been associated with a significant increase in the number of long-term cancer survivors [4]. For this reason, Dox is present in most chemotherapeutic cocktails, but its use is hampered by the serious dose-dependent side-effect of cardiotoxicity [5,6]. The life threatening Dox-induced cardiomyopathy is an important clinical problem. No satisfactory clinically applicable preventive treatment is presently available. The search for cardioprotective agents relies on the understanding of the molecular mechanisms involved and how to counteract them
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
