Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A

Hanna, Amy D.; Lam, Amanda; Tham, Steffi; Dulhunty, Angela F.; Beard, Nicole A.

doi:10.1124/mol.114.093849

Cited by 129 publications

(123 citation statements)

References 63 publications

Supporting

Mentioning

112

Contrasting

Unclassified

Order By: Relevance

“…Therefore, the changes in the threshold for SOICR are likely to be occurring at lower concentrations of H 2 O 2 within the cell. The presence of endogenous reducing agents, particularly with respect to the reversibility of the effect of oxidation, highlights the importance of extending previous single channel data on RyR2 thiol modifications (by doxorubicin (19,35)) and RyR1 oxidation (by H 2 O 2 (18)) to an intact cell model, and suggests that thiol modification induced irreversible inhibition of RyRs observed at the single-channel level is not an artifact of working with purified RyR channels. Notwithstanding, the irreversible nature of oxidation-induced SOICR inhibition in situ suggests it may be a pathological form of regulation, because RyR2 activity could only be recovered through the replacement of the oxidized channels.…”

Section: Discussionmentioning

confidence: 91%

Oxidation of RyR2 Has a Biphasic Effect on the Threshold for Store Overload-Induced Calcium Release

Waddell

Zhang

Hoeksema

et al. 2016

Biophysical Journal

View full text Add to dashboard Cite

At the single-channel level, oxidation of the cardiac ryanodine receptor (RyR2) is known to activate and inhibit the channel depending on the level of oxidation. However, the mechanisms through which these changes alter the activity of RyR2 in a cellular setting are poorly understood. In this study, we determined the effect of oxidation on a common form of RyR2 regulation; store overload-induced Ca(2+) release (SOICR). We found that oxidation resulted in concentration and time-dependent changes in the activation threshold for SOICR. Low concentrations of the oxidant H2O2 resulted in a decrease in the threshold for SOICR, which led to an increase in SOICR events. However, higher concentrations of H2O2, or prolonged exposure, reversed these changes and led to an increase in the threshold for SOICR. This increase in the threshold for SOICR in most cells was to such an extent that it led to the complete inhibition of SOICR. Acute exposure to high concentrations of H2O2 led to an initial decrease and then increase in the threshold for SOICR. In the majority of cells the increased threshold could not be reversed by the application of the reducing agent dithiothreitol. Therefore, our data suggest that low levels of RyR2 oxidation increase the channel activity by decreasing the threshold for SOICR, whereas high levels of RyR2 oxidation irreversibly increase the threshold for SOICR leading to an inhibition of RyR2. Combined, this indicates that oxidation regulates RyR2 by the same mechanism as phosphorylation, methylxanthines, and mutations, via changes in the threshold for SOICR.

show abstract

Section: Discussionmentioning

confidence: 91%

Oxidation of RyR2 Has a Biphasic Effect on the Threshold for Store Overload-Induced Calcium Release

Waddell

Zhang

Hoeksema

et al. 2016

Biophysical Journal

View full text Add to dashboard Cite

show abstract

“…Cardiomyocytes exposed to DOX are susceptible to impaired calcium handling, reducing the ability to control sarcoplasmic calcium concentrations, resulting in dysregulation of contraction and relaxation [12]. Therefore, we measured the expression of SERCA2a, a key calcium handling protein.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, protein expression of SERCA2a is reduced following exposure to DOX [12]. Reduced SERCA2a results in impaired calcium handling and myocardial performance [12,16]. However, exercise has been reported to increase SERCA2a protein content and improve cardiac function [8].…”

mentioning

confidence: 98%

“…Increased expression of antioxidant enzymes, heat shock protein (HSP), myosin heavy chain (MHC), and sarcoendoplasmic reticulum ATPase (SERCA2a) have been reported to contribute independently [20] or collectively [16] to the cardioprotection afforded by exercise. Specifically, protein expression of SERCA2a is reduced following exposure to DOX [12]. Reduced SERCA2a results in impaired calcium handling and myocardial performance [12,16].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Short-term exercise training attenuates acute doxorubicin cardiotoxicity

et al. 2015

View full text Add to dashboard Cite

Doxorubicin (DOX) is a potent and widely used antineoplastic agent. Despite the efficacy of DOX, its clinical use is limited by a dose-dependent cardiotoxicity. Chronic exercise training has been shown to protect against DOX-induced cardiotoxicity. It is less clear whether short-term exercise can attenuate DOX-induced dysfunction. The purposes of this study were to determine if short-term wheel running and treadmill exercise training can attenuate the cardiac dysfunction that accompanies DOX treatment and to investigate possible mechanisms that may be involved with any protective effects of exercise. Male Sprague-Dawley rats engaged in a short-term 5-day voluntary wheel running (WR) or treadmill exercise (TM) regimen. Following the exercise preconditioning period, animals received either 10 or 15 mg/kg of DOX or an equivalent volume of saline (SAL). Five days after DOX/SAL exposure, cardiac function was examined. Western immunoblotting was used to quantify left ventricular sarcoendoplasmic reticulum calcium-ATPase 2a (SERCA2a) protein expression. Exercise preconditioning attenuated in vivo and ex vivo cardiac dysfunction observed with DOX treatment alone. Specifically, short-term treadmill exercise (TM + DOX10, 56 ± 4%; TM + DOX15, 48 ± 5%) and voluntary wheel running (WR + DOX10, 51 ± 5%; WR + DOX15, 45 ± 3%) consistently preserved fractional shortening when compared to sedentary (SED) animals treated with DOX (SED + DOX10, 48 ± 4%; SED + DOX15, 39 ± 6%). Likewise, both exercise protocols preserved left ventricular developed pressure (TM + DOX10, 115 ± 6 mmHg; TM + DOX15, 85 ± 5 mmHg; WR + DOX10, 92 ± 12 mmHg; WR + DOX15, 91 ± 8 mmHg) when compared to SED animals treated with DOX (SED + DOX10, 79 ± 6 mmHg; SED + DOX15, 69 ± 7 mmHg). SERCA2a expression was also preserved in TM + DOX and WR + DOX. These findings suggest that short-term exercise prior to DOX treatment may be a valuable adjuvant therapy to offset acute cardiotoxicities and that maintaining calcium handling in cardiomyocytes may be responsible, in part, for the preservation in cardiac function.

show abstract

“…46,47 While the side effects of DXR on cardiomyocytes and its toxicity mechanism has been intensively studied, the effects of DXRol are not known. First, we measured the levels of DXRol produced from DXR-treated HepG2 and hCM cells (Fig.…”

Section: Staurosporine (Sts)mentioning

confidence: 99%

Integrated heart/cancer on a chip to reproduce the side effects of anti-cancer drugs in vitro

et al. 2017

View full text Add to dashboard Cite

Pre-clinical animal tests are used to assess drug efficacy and safety, but are limited by factors such as their suitability as a model for humans, robustness, cost, and ethical issues. While an organ-on-a-chip using human cells is promising for recapitulating human physiological conditions, it is highly desirable in investigations of the side effects of drugs to integrate more than one type of tissue using a designed circulatory system. We have developed a microfluidic device-an Integrated Heart/Cancer on a Chip (iHCC)-using human healthy heart cells (hCMs) and liver cancer cells (HepG2) to recapitulate the side effects of an anti-cancer drug, doxorubicin (DXR), to achieve individual cultures of cells from different tissues on a single device with three sets of artificial blood circulation loops, microfabrication technology for micro valves and a pump provides accurate fluid operation. Using improved soft lithography adopting numerical optimization simulation, the microfluidic device was fabricated with on-chip integration of pneumatic valves and a peristaltic micropump establishing precision fluid flow. The iHCC developed allows modelling of the side effects of DXR on heart cells caused by the production of toxic metabolites (doxorubicinol; DXRol) by HepG2 cells and the delivery of DXRol to heart cells via the circulation loop.Our findings open the door towards the development of a "Body-on-a-Chip."

show abstract

Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A

Cited by 129 publications

References 63 publications

Oxidation of RyR2 Has a Biphasic Effect on the Threshold for Store Overload-Induced Calcium Release

Oxidation of RyR2 Has a Biphasic Effect on the Threshold for Store Overload-Induced Calcium Release

Short-term exercise training attenuates acute doxorubicin cardiotoxicity

Integrated heart/cancer on a chip to reproduce the side effects of anti-cancer drugs in vitro

Contact Info

Product

Resources

About