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posted on 2025-06-04, 07:40 authored by Francisco J. Roa, Maria Roubelakis, Konstantinos Paschidis, Nils C.H. van Creij, Florian Handle, Manousos Makridakis, Shaman Narayanasamy, Irina-Afrodita Balaur, Aggeliki Tserga, Antonia Vlahou, Frédéric R. Santer, Per-Sonne Holm, Michele Hoffmann, Martin Puhr, Marika Mokou, Maria Frantzi, Reinhard Schneider, Agnieszka Latosinska, Harald Mischak, Venkata Satagopam, Zoran Culig, Renate Pichler <p>Amiodarone induces apoptosis in bladder cancer cell lines. Cells were treated for 48 or 72 hours with amiodarone (0, 25, and 50 μmol/L for UMUC3; 0, 12.5, and 25 μmol/L for HT1197, BFTC905, and RT112). <b>A,</b> Apoptosis was evaluated using the Caspase-Glo 3/7 Assay and viability using the CellTiter cell proliferation assay. Apoptosis results were normalized to viability. Data are presented as apoptosis related to the control and represent mean ± SEM from at least three independent experiments (one-way ANOVA with Dunnett’s multiple comparisons test; *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001; ****, <i>P</i> < 0.0001). <b>B,</b> Western blot analysis of cPARP expression after 48 hours of treatment with 0, 12.5, and 25 μmol/L amiodarone. GAPDH was used as a loading control. Blots are representative of three independent experiments. Quantification of cPARP expression (normalized by GAPDH) is indicated under each corresponding band. Values are presented as expression related to the control.</p>
History
ARTICLE ABSTRACT
Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the main treatment for muscle-invasive bladder cancer (MIBC). However, low survival rates highlight the necessity for new therapeutic strategies. Drug repurposing has emerged as a promising approach in cancer treatment, with various studies proposing the use of existing drugs for the treatment of bladder cancer. In this context, we previously established an in silico repurposing strategy using patient omics signatures, identifying drugs and compounds with the potential to reverse nonmuscle-invasive bladder cancer (NMIBC) to less aggressive subtypes. In the present study, we expanded our in silico approach to verify a list of compounds with potential antitumor activity against MIBC. We investigated the efficacy of the predicted candidates in a group of different bladder cancer cell lines, including NMIBC and MIBC. The most potent compound for decreasing cell viability was amiodarone, an antiarrhythmic drug widely used in the field of cardiology. Amiodarone reduced cell proliferation and colony formation capacity, with a stronger effect on the most aggressive invasive models, validating our repurposing pipeline. The drug additionally induced cell death and inhibited the activity of mTOR and its target protein S6, suggesting that the anticancer effect of the drug is, in part, mediated by inhibition of the mTOR signaling pathway. Furthermore, the administration of amiodarone in a xenograft MIBC mouse model reduced tumor growth without inducing toxicity. Altogether, we demonstrated that amiodarone is a potential repurposed drug for bladder cancer, which might be especially effective in MIBC.
Treatment of advanced bladder cancer remains a therapeutic challenge in urological oncology. In order to make more drugs available to patients in the future, we identified amiodarone, a repurposed drug used in cardiology as a compound that inhibits bladder cancer in vitro and in vivo.
