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Double benefit of metformin treatment: improved bladder function in cyclophosphamide-induced cystitis and enhanced cytotoxicity in cancer cells

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Abstract

Cyclophosphamide (CP) is a widely used anti-neoplastic drug; however, it leads to bladder dysfunction in the form of hemorrhagic cystitis that is a serious dose-limiting complication in cancer patients. We aimed to evaluate the protective effects of metformin (MET) in a mouse model of CP-related cystitis in parallel with its effect on CP-induced cytotoxicity in a breast cancer cell line, MDA-MB-231. Cystitis was induced by a single intraperitoneal injection of CP (300 mg/kg), and mice were administered MET, mesna, or vehicle treatment. 24 hours after cystitis induction, the bladders were removed for histopathological analysis and ex vivo evaluation of detrusor muscle contractility. The effect of MET on the cytotoxicity of CP in MDA-MB-231 cells was evaluated as the viability of the cells via MTT assay. Histopathological evaluation confirmed that CP induced a severe cystitis, and MET partially inhibited CP-induced bladder damage. Carbachol-evoked cholinergic contractions were significantly decreased in detrusor strips of mice injected with CP only compared to control (Emax=293.67± 20.00 vs. 497.79± 21.78 mg tension/mg tissue, respectively). In CP-injected mice, treatment with 100 mg/kg MET restored cholinergic contractions (Emax=473.72±62.61 mg tension/mg tissue). In MDA-MB-231 cells, MET decreased their viability, and the combination of MET and CP caused more decrease in cell viability as compared to CP alone (p<0.05), demonstrating that MET enhances the cytotoxicity of CP in these cancer cells. Our results indicate that MET has a strong potential as a therapeutic adjuvant to prevent CP-induced cystitis while enhancing the efficacy of CP.

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All data generated or analyzed during this study are included in this published article (and its supplementary information files).

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Funding

No funding was received for conducting this study.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, P.O: 61080, Trabzon, Turkey

    Seckin Engin, Elif Nur Barut & Sena Sezen

  2. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey

    Aysun Celik Soysal

  3. Department of Histology and Embryology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

    Oguzhan Keskin & Gokcen Kerimoglu

  4. Department of Medical Pharmacology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

    Mine Kadioglu

  5. Drug and Pharmaceutical Technology Application and Research Center, Karadeniz Technical University, Trabzon, Turkey

    Sena Sezen

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  1. Seckin Engin
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Contributions

SE conceived and designed the research. SE, ENB, ACS, OK, and GK conducted experiments. SE, MK, and SS analyzed the data and wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Seckin Engin.

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The study was approved by the Institutional Animal Care and Use Committee (protocol no. 2018/39).

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Engin, S., Barut, E.N., Soysal, A.C. et al. Double benefit of metformin treatment: improved bladder function in cyclophosphamide-induced cystitis and enhanced cytotoxicity in cancer cells. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1167–1175 (2021). https://doi.org/10.1007/s00210-021-02055-9

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