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Small-molecule screening of PC3 prostate cancer cells identifies tilorone dihydrochloride to selectively inhibit cell
Michel D Wissing1, Tikva Dadon1, Eunice Kim1
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Abstract:
Cyclin-dependent kinase 5 (CDK5) is a potential target for prostate cancer treatment, the enzyme being essential for prostate tumor growth and formation of metastases. In the present study, we identified agents that target prostate cancer cells based on CDK5 expression. CDK5 activity was suppressed by transfection of PC3 prostate cancer cells with a dominant-negative construct (PC3 CDK5dn). PC3 CDK5dn and PC3 control cells were screened for compounds that selectively target cells based on CDK5 expression, utilizing the Johns Hopkins Drug Library. MTS proliferation, clonogenic and 3D growth assays were performed to validate the selected hits. Screening of 3,360 compounds identified rutilantin, ethacridine lactate and cetalkonium chloride as compounds that selectively target PC3 control cells and a tilorone analog as a selective inhibitor of PC3 CDK5dn cells. A PubMed literature study indicated that tilorone may have clinical use in patients. Validation experiments confirmed that tilorone treatment resulted in decreased PC3 cell growth and invasion; PC3 cells with inactive CDK5 were inhibited more effectively. Future studies are needed to unravel the mechanism of action of tilorone in CDK5 deficient prostate cancer cells and to test combination therapies with tilorone and a CDK5 inhibitor for its potential use in clinical practice.
Insights
Researchers identified compounds targeting prostate cancer cells by targeting Cyclin-dependent kinase 5 (CDK5). Tilorone selectively inhibited CDK5-deficient cells, showing potential for clinical use in prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinase 5 (CDK5) is crucial for prostate tumor growth and metastasis.
- Targeting CDK5 presents a potential therapeutic strategy for prostate cancer.
Purpose of the Study:
- To identify novel compounds that selectively target prostate cancer cells based on CDK5 expression.
- To evaluate the efficacy of identified compounds, particularly tilorone, in preclinical models.
Main Methods:
- Prostate cancer cells (PC3) were transfected with a dominant-negative CDK5 construct.
- High-throughput screening of the Johns Hopkins Drug Library (3,360 compounds) was performed.
- Cell proliferation, clonogenic, and 3D growth assays were used for validation.
Main Results:
- Rutilantin, ethacridine lactate, and cetalkonium chloride selectively targeted control PC3 cells.
- A tilorone analog selectively inhibited PC3 cells with suppressed CDK5 activity (PC3 CDK5dn).
- Tilorone treatment reduced PC3 cell growth and invasion, with greater efficacy in CDK5-inactive cells.
Conclusions:
- Tilorone demonstrates selective efficacy against prostate cancer cells with reduced CDK5 activity.
- Tilorone shows potential for clinical application in prostate cancer therapy.
- Further research is warranted to elucidate tilorone's mechanism of action and explore combination therapies.