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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Future Oncotargets: Targeting Overexpressed Conserved Protein Targets in Androgen Independent Prostate Cancer Cell
Abdul M Baig1, Zohaib Rana1, Mohammad M Mannan2
1Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan.
Background:
Targeting evolutionarily conserved proteins in malignant cells and the adapter proteins involved in signalling that generates from such proteins may play a cardinal role in the selection of anti-cancer drugs. Drugs targeting these proteins could be of importance in developing anti-cancer drugs.
Objectives:
We inferred that drugs like loperamide and promethazine that act as antagonists of proteins conserved in cancer cells like voltage-gated Calcium channels (Cav), Calmodulin (CaM) and drug efflux (ABCB1) pump may have the potential to be re-purposed as an anti-cancer agent in Prostate Cancer (PCa).
Methods:
Growth and cytotoxic assays were performed by selecting loperamide and promethazine to target Cav, CaM and drug efflux (ABCB1) pumps to elucidate their effects on androgen-independent PC3 and DU145 PCa cell lines.
Result:
We show that loperamide and promethazine in doses of 80-100μg/ml exert oncocidal effects when tested in DU145 and PC3 cell lines. Diphenhydramine, which shares its targets with promethazine, except the CaM, failed to exhibit oncocidal effects.
Conclusion:
Anti-cancer effects can be of significance if structural analogues of loperamide and promethazine that specifically target Cav, CaM and ABCB1 drug efflux pumps can be synthesized, or these two drugs could be re-purposed after human trials in PCa.
Insights
Loperamide and promethazine show potential as anti-cancer agents for prostate cancer by targeting conserved proteins. Further research and human trials could validate their repurposing for treating this disease.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Targeting evolutionarily conserved proteins in cancer cells is crucial for anti-cancer drug development.
- Adapter proteins in signaling pathways are key targets for novel anti-cancer therapies.
Purpose of the Study:
- To investigate the potential repurposing of loperamide and promethazine as anti-cancer agents for prostate cancer.
- To evaluate the efficacy of these drugs in targeting voltage-gated Calcium channels (Cav), Calmodulin (CaM), and the ABCB1 drug efflux pump in prostate cancer cells.
Main Methods:
- Growth and cytotoxic assays were conducted on androgen-independent PC3 and DU145 prostate cancer cell lines.
- Loperamide and promethazine were used to target Cav, CaM, and ABCB1 pumps.
Main Results:
- Loperamide and promethazine demonstrated oncocidal effects at doses of 80-100μg/ml in DU145 and PC3 cell lines.
- Diphenhydramine, lacking CaM targeting, did not exhibit oncocidal effects, highlighting the importance of specific targets.
Conclusions:
- Loperamide and promethazine show promise for prostate cancer treatment, potentially through repurposing after human trials.
- Developing structural analogues that specifically target Cav, CaM, and ABCB1 pumps could enhance anti-cancer efficacy.
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