Roa Francisco J, Roubelakis Maria, Paschidis Konstantinos, van Creij Nils C H, Handle Florian, Makridakis Manousos, Narayanasamy Shaman, Balaur Irina-Afrodita, Tserga Aggeliki, Vlahou Antonia, Santer Frédéric R, Holm Per-Sonne, Hoffmann Michele, Puhr Martin, Mokou Marika, Frantzi Maria, Schneider Reinhard, Latosinska Agnieszka, Mischak Harald, Satagopam Venkata, Culig Zoran, Pichler Renate
Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Cancer Res Commun. 2025 Jun 1;5(6):906-920. doi: 10.1158/2767-9764.CRC-24-0433.
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.
基于顺铂的新辅助化疗后行根治性膀胱切除术是肌肉浸润性膀胱癌（MIBC）的主要治疗方法。然而，低生存率凸显了新治疗策略的必要性。药物再利用已成为癌症治疗中一种有前景的方法，各种研究提出使用现有药物治疗膀胱癌。在此背景下，我们之前建立了一种利用患者组学特征的计算机再利用策略，确定了有可能将非肌肉浸润性膀胱癌（NMIBC）逆转为侵袭性较低亚型的药物和化合物。在本研究中，我们扩展了计算机方法，以验证一系列对MIBC具有潜在抗肿瘤活性的化合物。我们在一组不同的膀胱癌细胞系中研究了预测候选药物的疗效，包括NMIBC和MIBC。降低细胞活力最有效的化合物是胺碘酮，这是一种广泛应用于心脏病学领域的抗心律失常药物。胺碘酮降低了细胞增殖和集落形成能力，对侵袭性最强的模型影响更强，验证了我们的再利用流程。该药物还诱导细胞死亡并抑制mTOR及其靶蛋白S6的活性，表明该药物的抗癌作用部分是通过抑制mTOR信号通路介导的。此外，在异种移植MIBC小鼠模型中给予胺碘酮可降低肿瘤生长且不诱导毒性。总之，我们证明胺碘酮是一种潜在的用于膀胱癌的再利用药物，可能对MIBC特别有效。
晚期膀胱癌的治疗仍然是泌尿外科肿瘤学中的一个治疗挑战。为了在未来为患者提供更多药物，我们确定了胺碘酮，一种用于心脏病学的再利用药物，作为一种在体外和体内均能抑制膀胱癌的化合物。
