Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer

Repurposing FDA‐approved, antipsychotic cationic amphiphilic drugs like penfluridol dose‐dependently decreased viability of human bladder cancer cells, significantly reduced tumor progression and metastasis in an orthotopic human bladder cancer xenograft model, and induced significant antitumor resp...

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Bibliographic Details
Published in:Molecular oncology 2020-12, Vol.14 (12), p.3121-3134
Main Authors: Horst, Geertje, Merbel, Arjanneke F., Ruigrok, Eline, Mark, Maaike H., Ploeg, Emily, Appelman, Laura, Tvingsholm, Siri, Jäätelä, Marja, Uhm, Janneke, Kruithof‐de Julio, Marianna, Thalmann, George N., Pelger, Rob C. M., Bangma, Chris H., Boormans, Joost L., Pluijm, Gabri, Zwarthoff, Ellen C.
Format: Article
Language:English
Subjects:
Animal care
Animal models
Antitumor activity
Apoptosis
Bladder
Bladder cancer
Breast
Cancer therapies
cationic amphiphilic drugs
Cell death
Chemotherapy
Colon
Cytotoxicity
Drug dosages
ex vivo culture
Histology
Lung cancer
Lung carcinoma
Metastasis
Pancreas
Pancreatic carcinoma
penfluridol
preclinical in vivo model
Proliferating cell nuclear antigen
Schizophrenia
Transformed cells
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Summary:Repurposing FDA‐approved, antipsychotic cationic amphiphilic drugs like penfluridol dose‐dependently decreased viability of human bladder cancer cells, significantly reduced tumor progression and metastasis in an orthotopic human bladder cancer xenograft model, and induced significant antitumor responses in patient‐derived, ex vivo cultured bladder cancer tissue. Clinically approved penfluridol is a promising antineoplastic agent for bladder cancer patients for which effective therapy is currently lacking. More effective therapy for patients with either muscle‐invasive or high‐risk non‐muscle‐invasive urothelial carcinoma of the bladder (UCB) is an unmet clinical need. For this, drug repositioning of clinically approved drugs represents an interesting approach. By repurposing existing drugs, alternative anticancer therapies can be introduced in the clinic relatively fast, because the safety and dosing of these clinically approved pharmacological agents are generally well known. Cationic amphiphilic drugs (CADs) dose‐dependently decreased the viability of a panel of human UCB lines in vitro. CADs induced lysosomal puncta formation, a hallmark of lysosomal leakage. Intravesical instillation of the CAD penfluridol in an orthotopic mouse xenograft model of human UCB resulted in significantly reduced intravesical tumor growth and metastatic progression. Furthermore, treatment of patient‐derived ex vivo cultured human UCB tissue caused significant partial or complete antitumor responses in 97% of the explanted tumor tissues. In conclusion, penfluridol represents a promising treatment option for bladder cancer patients and warrants further clinical evaluation.
ISSN:1574-7891
1878-0261
DOI:10.1002/1878-0261.12793