Development of peptide-based reversing agents for p-glycoprotein-mediated resistance to carfilzomib
Lin Ao1, Ying Wu, Donghern Kim
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
Abstract:
Carfilzomib is a novel class of peptidyl epoxyketone proteasome inhibitor and has demonstrated promising activity in multiple clinical trials to treat patients with multiple myeloma and other types of cancers. Here, we investigated molecular mechanisms underlying acquired resistance to carfilzomib and a potential strategy to restore cellular sensitivity to carfilzomib. H23 and DLD-1 cells (human lung and colon adenocarcinoma cell lines) with acquired resistance to carfilzomib displayed marked cross-resistance to YU-101, a closely related proteasome inhibitor, and paclitaxel, a known substrate of Pgp. However, carfilzomib-resistant cells remained sensitive to bortezomib, a clinically used dipeptide with boronic acid pharmacophore. In accordance with these observations, carfilzomib-resistant H23 and DLD-1 cells showed marked upregulation of P-glycoprotein (Pgp) as compared to their parental controls, and coincubation with verapamil, a Pgp inhibitor, led to an almost complete restoration of cellular sensitivity to carfilzomib. These results indicate that Pgp upregulation plays a major role in the development of carfilzomib resistance in these cell lines. In developing a potential strategy to overcome carfilzomib resistance, we as a proof of concept prepared a small library of peptide analogues derived from the peptide backbone of carfilzomib and screened these molecules for their activity to restore carfilzomib sensitivity when cotreated with carfilzomib. We found that compounds as small as dipeptides are sufficient in restoring carfilzomib sensitivity. Taken together, we found that Pgp upregulation plays a major role in the development of resistance to carfilzomib in lung and colon adenocarcinoma cell lines and that small peptide analogues lacking the pharmacophore can be used as agents to reverse acquired carfilzomib resistance. Our findings may provide important information in developing a potential strategy to overcome drug resistance.
Insights
Acquired resistance to carfilzomib in cancer cells is often due to P-glycoprotein (Pgp) upregulation. Small peptide analogues can restore sensitivity to carfilzomib, offering a strategy to overcome drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Carfilzomib, a proteasome inhibitor, shows efficacy in treating multiple myeloma and other cancers.
- Acquired resistance to cancer therapeutics is a significant clinical challenge.
- Understanding resistance mechanisms is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to carfilzomib.
- To identify strategies for restoring cellular sensitivity to carfilzomib in resistant cancer cells.
- To evaluate the role of P-glycoprotein (Pgp) in carfilzomib resistance.
Main Methods:
- Utilized human lung and colon adenocarcinoma cell lines (H23 and DLD-1) with acquired carfilzomib resistance.
- Assessed cross-resistance patterns with other proteasome inhibitors and chemotherapeutics.
- Quantified P-glycoprotein (Pgp) expression levels in resistant versus parental cells.
- Investigated the effect of verapamil, a Pgp inhibitor, on carfilzomib sensitivity.
- Synthesized and screened peptide analogues of carfilzomib for their ability to restore sensitivity.
Main Results:
- Carfilzomib-resistant cells exhibited cross-resistance to YU-101 and paclitaxel but remained sensitive to bortezomib.
- Marked upregulation of P-glycoprotein (Pgp) was observed in carfilzomib-resistant H23 and DLD-1 cells.
- Verapamil treatment restored cellular sensitivity to carfilzomib in resistant cells, indicating Pgp's role.
- Small peptide analogues, including dipeptides, effectively restored carfilzomib sensitivity when used in combination therapy.
Conclusions:
- P-glycoprotein (Pgp) upregulation is a key mechanism driving acquired resistance to carfilzomib in lung and colon adenocarcinoma cell lines.
- Small peptide analogues, distinct from the carfilzomib pharmacophore, can serve as effective agents to reverse acquired carfilzomib resistance.
- These findings offer a promising strategy for overcoming drug resistance in cancer therapy.
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