Histopathologic and molecular comparative analyses of intravesical Aurora kinase-A inhibitor Alisertib with bacillus Calmette-Guérin on precancerous lesions of bladder in a rat model

Recent studies have shown that Aurora-A expression is associated with bladder cancer initiation and progression. In this study, the effects of intravesical Aurora-A inhibitor Alisertib (ALS) and bacillus Calmette–Guerin (BCG) were compared on bladder carcinogenesis. Two mg N-Methyl-N-nitrosourea was administered intravesically to forty of Wistar-albino rats every other week for 8 weeks. At week 10, rats were divided into four groups (10/group): No-treatment (vehicle), ALS-alone, BCG-alone, and ALS + BCG. The intravesical treatment of ALS, BCG, and ALS plus BCG was performed once a week for 6 weeks. At week 16, bladders were collected for immunohistopathological and Western blot analysis. The cell cycle regulators p53, p21, Aurora-A, phosphorylated Aurora-A (p-Aurora-A), and apoptotic marker cleavage of poly [ADP-ribose] polymerase (c-PARP) were determined by Western blot. Histopathologically relatively healthy urothelium was observed in ALS + BCG group (87.5%) compared to the ALS-alone (50%) and the BCG-alone (50%) groups. The lowest expression of p21 and p53 was detected in the BCG-alone, while the highest level of expression was evident in no-treatment group. The ALS treatment alone caused a slight decrease in Aurora-A while there was a dramatic decrease in p-Aurora-A in comparison to no-treatment group. In overall combined treatment with ALS + BCG significantly increased c-PARP compared to all mono-treatments, and decreased all cell cycle parameters compared to no-treatment group. Although intravesical ALS treatment has similar antiproliferative effects like BCG, ALS + BCG combined treatment led to a best histopathologic and apoptotic response. Consequently, BCG combined with Aurora-A inhibition may provide a new intravesical treatment modality in the prevention of bladder carcinogenesis.