| RRC ID |
27891
|
| Author |
Sishi BJ, Loos B, van Rooyen J, Engelbrecht AM.
|
| Title |
Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity.
|
| Journal |
Toxicology
|
| Abstract |
Anthracycline-induced cardiotoxicity is a clinically complex syndrome that leads to substantial morbidity and mortality for cancer survivors. Despite several years of research, the underlying molecular mechanisms remain largely undefined and thus effective therapies to manage this condition are currently non-existent. This study therefore aimed to determine the contribution of the ubiquitin-proteasome pathway (UPP) and endoplasmic reticulum (ER)-stress within this context. Cardiotoxicity was induced with the use of doxorubicin (DXR) in H9C2 rat cardiomyoblasts (3 μM) for 24 h, whereas the tumour-bearing GFP-LC3 mouse model was treated with a cumulative dose of 20 mg/kg. Markers for proteasome-specific protein degradation were significantly upregulated in both models following DXR treatment, however proteasome activity was lost. Moreover, ER-stress as assessed by increased ER load was considerably augmented (in vitro) with modest binding of DXR with ER. These results suggest that DXR induces intrinsic activation of the UPP and ER stress which ultimately contributes to dysfunction of the myocardium during this phenomenon.
|
| Volume |
309
|
| Pages |
23-9
|
| Published |
2013-7-5
|
| DOI |
10.1016/j.tox.2013.04.016
|
| PII |
S0300-483X(13)00120-0
|
| PMID |
23639627
|
| MeSH |
Animals
Cardiotoxins / pharmacology*
Doxorubicin / pharmacology*
Enzyme Activation / drug effects*
Enzyme Activation / physiology
Female
Mice
Mice, Transgenic
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / enzymology
Proteasome Endopeptidase Complex / metabolism*
Proteasome Inhibitors / pharmacology*
Random Allocation
Rats
Ubiquitination / drug effects*
Ubiquitination / physiology
|
| IF |
4.099
|
| Times Cited |
26
|
|
WOS Category
|
PHARMACOLOGY & PHARMACY
TOXICOLOGY
|
| Resource |
| Mice |
RBRC00806 |
