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Boosting bladder cancer treatment by intravesical nitazoxanide and bacillus calmette-guérin association

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Abstract

Purpose

Nitazoxanide (NTZ) has shown a promising antitumoral effect, the current study compared the anti-neoplastic effects of intravesical NTZ and BCG plus NTZ in NMIBC animal model.

Methods

30 rats, Fisher 344 were instilled with 4 intravesical doses of 1.5 mg/kg of N-methyl-N-nitrosourea (MNU) every 15 days for BC induction. The animals were divided into 3 groups (Group BCG 106 UFC – 1 mg of BCG; Group NTZ – 300 mg/kg of NTZ; Group NTZ + BCG – simultaneous treatment of BCG and NTZ) and received weekly intravesical treatment for 6 consecutive weeks. Animals were submitted to ultrasound imaging and euthanasia, their bladders were collected and histopathological, immunohistochemical tests (ki67 e c-Myc) and Western Blotting (PI3K, mTOR, and p-4E-BP) were performed.

Results

Histopathological tests showed 66.67%, 62.5% and 37.5% incidence of BC in animals treated with BCG, NTZ, and NTZ + BCG, respectively. Nuclear positivity for ki-67 in BC animals were 12.4% (IC 10.1–14.6%), 13.2% (IC 10.5–15.9%) and 8.8% (IC 6.0–11.6%) in BCG, NTZ and NTZ + BCG group, respectively (p = 0.063). Between animals with carcinoma, c-Myc strong positive was 40.10% in NTZ, 32.2% in BCG and 19.90% in the NTZ + BCG group (p < 0.001). Blotting has shown mTOR (p = 0.0473) and PI3K inhibition (p = 0.0349) in the presence of BCG, added to 4-EBP inhibition in the presence of NTZ (p = 0.0004).

Conclusions

Results show the possible synergy between the gold standard BC treatment BCG and NTZ, in which multiple targets inhibition such as c-Myc and downstream mTOR, p-4E-BP and PI3K might play a role.

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Funding

CAPES Foundation, grant: 23038.005289/2017-88 (Reis LO). National Council for Scientific and Technological Development – CNPq, Research Productivity: 302,622/2015–2 and 304,747/2018–1 (Reis LO). FAEPEX, University of Campinas: 7517/2018 (Ikari O).

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Authors and Affiliations

  1. UroScience, University of Campinas, Unicamp, Campinas, São Paulo, Brazil

    Isis G. A. Kiehl, Eduardo Riccetto, Ana C. C. Salustiano, Marina V. Ossick, Heloisa B. Assalin & Osamu Ikari

  2. School of Medical Sciences, Pontifical Catholic University of Campinas (PUC-Campinas) and UroScience, University of Campinas (Unicamp), R. John Boyd Dunlop, s/n, Campinas, São Paulo, Brasil, CEP, 13060-904

    Leonardo O. Reis

Authors
  1. Isis G. A. Kiehl
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  2. Eduardo Riccetto
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  3. Ana C. C. Salustiano
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  4. Marina V. Ossick
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  5. Karen L. Ferrari
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  7. Osamu Ikari
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Contributions

Isis G.A. Kiehl: data collection, data analysis, and manuscript writing/editing. Eduardo Ricetto: data collection, data analysis, and manuscript writing/editing. Ana C.C. Salustiano: data collection, and manuscript editing. Marina V. Ossick: data collection, and manuscript editing. Karen L. Ferrari: data collection, and manuscript editing. Heloisa B. Assalin: data collection, data analysis, and manuscript editing. Osamu Ikari: funding acquisition, data analysis, manuscript editing. Leonardo O. Reis: project development, funding acquisition, data analysis, manuscript writing/editing.

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Correspondence to Leonardo O. Reis.

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Research involving animals

The local research ethics committee approved the protocol (nº 4540-1/2017).

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Kiehl, I.G.A., Riccetto, E., Salustiano, A.C.C. et al. Boosting bladder cancer treatment by intravesical nitazoxanide and bacillus calmette-guérin association. World J Urol 39, 1187–1194 (2021). https://doi.org/10.1007/s00345-020-03294-w

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