Doxorubicin induces detrusor smooth muscle impairments through myosin dysregulation, leading to a risk of lower urinary tract dysfunction
Nao Iguchi, PhD1, M. İrfan Dönmez, MD1, Alonso Carrasco, Jr., MD2, Duncan Wilcox, MD2, Ricardo Pineda, PhD1, Anna Malykhina, PhD1, Nicholas Cost, MD2.
1University of Colorado AMC, Aurora, CO, USA, 2Children's Hospital Colorado, Aurora, CO, USA.
BACKGROUND: Cytotoxic chemotherapy is the foundation for treating the wide variety of childhood malignancies, however, these therapies are known to have a variety of deleterious side effects. One common chemotherapy used in children, doxorubicin (DOX) is well known to cause cardiotoxicity and cardiomyopathy mainly through oxidative stress. Recent studies revealed that doxorubicin impairs skeletal and smooth muscle function, and contributes to fatigue and abnormal intestinal motility in patients. In this study, we tested the hypothesis that systemic doxorubicin administration also affects detrusor smooth muscle function in the urinary bladder, especially when administered at a young age.
METHODS: Using IACUC approved protocols, we investigated the effects of DOX on the detrusor smooth muscle and bladder function were assessed in BALB/cJ mice that received 6 weekly intravenous injections of doxorubicin (3mg/kg) or saline for the control group. Bladder histology, in vitro evaluation of detrusor contractility, and gene expression studies were performed at 1 week after the last drug administration.
RESULTS: Systemic DOX administration resulted in detrusor smooth muscle hypertrophy by 1.2-fold (p<0.05) and a significant attenuation of detrusor smooth muscle contractility (decreased by 25-32%, p<0.05) followed by a slower relaxation compared to the control group (Figure 1). Gene expression analyses reveled that unlike doxorubicin-induced cardiotoxicity, the bladders from doxorubicin-administered animals showed no changes in oxidative stress markers, instead, downregulation of large conductance/big potassium (BK) channel and altered expression of myosin light chain kinase (Mlck) coincided with reduced myosin light chain phosphorylation (P-Myl9, Figure 2), indicating that DOX-induced DSM dysfunction is mainly myogenic. CONCLUSIONS: The results indicate that in vivo doxorubicin exposure caused detrusor smooth muscle dysfunction by dysregulation of the detrusor contractile-relaxation mechanisms through molecular pathways different from oxidative stress. Since many of the cancer late effects occur years after therapy, our findings suggest increasing awareness that childhood cancer survivors treated with DOX may be at increased risk of bladder dysfunction and accordingly monitor those patients closely.
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