Identification of a novel cisplatin resistance gene in bladder cancer and potential inhibitors

Year 2025, Volume: 29 Issue: 6, 2278 - 2286, 02.11.2025

Kiarash Zohori Pour Marjan Fallah Shirin Hekmatirad

https://doi.org/10.12991/jrespharm.1797763

Abstract

Cisplatin-based regimens are indicated for the treatment of a broad spectrum of solid malignancies. Bladder cancer is among the solid malignancies in which cisplatin is used as the first-line treatment. Despite the high success rate of cisplatin therapy, a subset of patients experience poor prognosis and develop resistance to cisplatin. For this reason, there is still a need to find new drug targets to overcome cisplatin resistance and improve response in patients with bladder cancer. This study aimed to find a potential target to help restore bladder cancer sensitivity to cisplatin. First, two microarray datasets were analyzed to find the gene signatures related to cisplatin resistance. Akinase anchor protein 5 (AKAP5) gene was selected as a possible target in cisplatin resistance. To find a suitable AKAP5 inhibitor, a virtual screening of a FDA-approved library was performed and 5-methyltetrahydrofolate (5-MTHF) was selected for the subsequent investigation. Finally, the effect of AKAP inhibition on the cytotoxicity of cisplatin in 5637 cells was determined using the MTT assay. Molecular docking of the selected inhibitor against AKAP5 was performed to validate the virtual screening results and the docking scores were in line with the virtual screening results. Cotreatment with 5-MTHF significantly increased cytotoxicity in 5637 cells treated with 2.5 μM of cisplatin, compared to the groups not receiving 5-MTHF (P<0.05). Our results showed the effectiveness of AKAP5 inhibition to overcome cisplatin resistance in bladder cancer. This novel approach holds the potential for optimizing therapeutic outcomes in bladder cancer patients.

Keywords

Cisplatin , AKAP5 , Chemotherapy resistance , 5-methyl tetrahydrofolate , Bladder cancer

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