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Abstract
Doxorubicin (Dox) is an effective chemotherapeutic agent used in the treatment of various cancers. Its clinical use is often limited due to its potentially fatal cardiotoxic side effect. Increasing evidence indicates that tumour protein p53 (p53), adenosine monophosphate-activated protein kinase (AMPK), nucleoporin p62 (p62), and the mammalian target of rapamycin (mTOR) are critical mediators of Dox-induced apoptosis, and subsequent dysregulation of autophagy. Aspalathin, a polyphenolic dihydrochalcone C-glucoside has been shown to activate AMPK while decreasing the expression of p53. However, the role that aspalathin could play in the inhibition of Dox-induced cardiotoxicity through increased autophagy flux remained unexplored. H9c2 cardiomyocytes and Caov-3 ovarian cancer cells were cultured in Dulbecco’s Modified Eagle’s medium and treated with or without Dox for five days. Thereafter, cells exposed to 0.2 µM Dox were co-treated with either 20 µM Dexrazozane (Dexra) or 0.2 µM aspalathin (ASP) daily for 5 days. Results obtained showed that ASP mediates its cytoprotective effect in a p53-dependent manner, by increasing the Bcl-2/Bax ratio and decreasing apoptosis. The latter effect was diminished through ASP-induced activation of autophagy-related genes (Atgs) with an associated decrease in p62 through induction of AMPK and Fox01. Furthermore, we showed that ASP was able to potentiate this effect without decreasing the anti-cancer efficacy of Dox, as could be observed in Caov-3 ovarian cancer cells. Taken together, the data presented in this study provides a credible mechanism by which ASP co-treatment could protect the myocardium from Dox-induced cardiotoxicity.
Highlights
Tumour suppressor protein (p53), known as the cellular gatekeeper, is a phospho protein that is activated in response to various stresses including DNA damage, oxidative stress, chronic starvation, endoplasmic reticulum stress and hypoxia [1]
Results obtained showed that Dox treatment decreased expression of light chain 3 (LC3)-II (38.71 ± 2.1%, p ≤ 0.001), suggesting inhibition of autophagy upon Dox treatment when compared to the untreated control
Autophagy can be defined as a process cells use to clear damaged proteins and organelles [19]
Summary
Tumour suppressor protein (p53), known as the cellular gatekeeper, is a phospho protein that is activated in response to various stresses including DNA damage, oxidative stress, chronic starvation (nutrient deprivation), endoplasmic reticulum stress and hypoxia [1]. P53 orchestrates a signaling cascade that induces the initiation of apoptosis and autophagy. Apoptosis and autophagy are important cellular processes known to play a central role in the maintenance and homeostasis of various biological signals. Molecules 2017, 22, 1589 through programmed cell death, autophagy maintains cellular homeostasis through the segregation and delivery of damaged intracellular organelles and molecules to the lysosome machinery for proteolytic degradation [2,3,4]. The machinery includes activation of various autophagy-related genes (Atgs). Atgs complexes with the non-soluble microtubule-associated protein 1 light chain 3 (LC3) to increase autophagic flux through decreased expression of sequestosome 1
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