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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

  • Urology - Original Paper
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Abstract

Purpose

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–Guérin (BCG) were compared on bladder carcinogenesis.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

The study was funded by the Scientific and Investigational Projects Reserve of the University of Kocaeli (Grant number 2015/035).

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Authors and Affiliations

  1. Department of Urology, Kocaeli University School of Medicine, 41380, Kocaeli, Turkey

    Kerem Teke, Hasan Yilmaz, Ali Kemal Uslubas & Ozdal Dillioglugil

  2. Department of Medical Biology, Kocaeli University School of Medicine, Kocaeli, Turkey

    Gurler Akpinar, Murat Kasap & Nil Guzel

  3. Department of Pharmacology, Kocaeli University School of Medicine, Kocaeli, Turkey

    Oguz Mutlu

  4. Department of Pathology, Kocaeli University School of Medicine, Kocaeli, Turkey

    Demir Kursat Yildiz

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  1. Kerem Teke
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Correspondence to Kerem Teke.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Teke, K., Yilmaz, H., Uslubas, A.K. et al. 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. Int Urol Nephrol 50, 1417–1425 (2018). https://doi.org/10.1007/s11255-018-1914-x

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