Inflammation may play a causal role in urological side effects reported following intravesical mitomycin C (MMC). Our aim was to investigate the effects of the non-steroidal anti-inflammatory drug ibuprofen (IBU) on the cytotoxic potency of MMC and the potential for IBU to protect against bladder dysfunction. Malignant (RT4, T24) and normal (UROtsa) urothelial lines were treated with MMC followed by ibuprofen, with cell viability and caspase-3 activity assessed. Female C57BL/6JArc mice (Saline/Control, MMC, Saline + IBU and MMC + IBU), received intravesical treatment (1hr) with saline or MMC (2mg/mL), with IBU (1mg/mL) delivered in drinking water (for 7-days). Voiding pattern analysis was conducted prior to and following (1,3,7 days) treatment. A whole bladder preparation was used to assess compliance, contractile responses and urothelial mediator release. Ibuprofen selectively increased the cytotoxic potency of MMC and caspase-3 activity in both malignant cells lines but not in UROtsa. MMC significantly increased voiding frequency at 24 hours and 3 days, while administration of ibuprofen significantly reduced this effect. MMC significantly increased the frequency of spontaneous contractions from 2.3±0.5 contractions/min in saline controls to 4.8 ±0.16 contractions/min, with ibuprofen protecting against this change. Interestingly, while nerve evoked responses were not altered by MMC, they were increased in both IBU groups. Ibuprofen improved voiding dysfunction following MMC treatment through reducing spontaneous phasic activity and enhancing nerve mediated contractions. Ibuprofen use in bladder cancer patients may help to minimise the urological adverse effects associated with intravesical MMC.
The Journal of pharmacology and experimental therapeutics. 2018 May 21 [Epub ahead of print]
Eliza G West, Ryan Lang, Donna Sellers, Russ Chess-Williams, Catherine M McDermott
Bond University., Bond University .