ArticleMolecular pharmaceutics2012
Development of peptide-based reversing agents for p-glycoprotein-mediated resistance to carfilzomib.
Article in Molecular pharmaceutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 55 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- An odyssey of monoclonal gammopathies: focusing on precursors and the progression from MGUS and SMM to multiple Myeloma, with a brief overview of novel therapeutic strategies.Clinical and experimental medicine · 2026Review
- Brain-Permeable Immunoproteasome-Targeting Macrocyclic Peptide Epoxyketones for Alzheimer's Disease.Journal of medicinal chemistry · 2024Article
- Carfilzomib-Loaded Ternary Polypeptide Nanoparticles Stabilized by Polycationic Complexation.Journal of pharmaceutical sciences · 2024Article
- Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives.Cancers · 2023Review
- Size optimization of carfilzomib nanocrystals for systemic delivery to solid tumors.Journal of controlled release : official journal of the Controlled Release Society · 2022Article
- Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance.Molecules (Basel, Switzerland) · 2022Review
- Bortezomib- and carfilzomib-resistant myeloma cells show increased activity of all three arms of the unfolded protein response.American journal of cancer research · 2022Article
- Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease.Journal of medicinal chemistry · 2021Article
- Drug and Solute Transporters in Mediating Resistance to Novel Therapeutics in Multiple Myeloma.ACS pharmacology & translational science · 2021Review
- Inhibition of P-Glycoprotein Does Not Increase the Efficacy of Proteasome Inhibitors in Multiple Myeloma Cells.ACS pharmacology & translational science · 2021Article
- Proteasomal adaptations to FDA-approved proteasome inhibitors: a potential mechanism for drug resistance?Cancer drug resistance (Alhambra, Calif.) · 2021Article
- Ternary Polypeptide Nanoparticles with Improved Encapsulation, Sustained Release, and Enhanced In Vitro Efficacy of Carfilzomib.Pharmaceutical research · 2020Article
- Enhanced O-GlcNAcylation Mediates Cytoprotection under Proteasome Impairment by Promoting Proteasome Turnover in Cancer Cells.iScience · 2020Article
- Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.International journal of molecular sciences · 2019Article
- Development of Novel Epoxyketone-Based Proteasome Inhibitors as a Strategy To Overcome Cancer Resistance to Carfilzomib and Bortezomib.Journal of medicinal chemistry · 2019Article
- A Practical Review of Proteasome Pharmacology.Pharmacological reviews · 2019Review
- H727 cells are inherently resistant to the proteasome inhibitor carfilzomib, yet require proteasome activity for cell survival and growth.Scientific reports · 2019Article
- Next-generation proteasome inhibitors for cancer therapy.Translational research : the journal of laboratory and clinical medicine · 2018Review
- Characterization of carfilzomib-resistant non-small cell lung cancer cell lines.Journal of cancer research and clinical oncology · 2018Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.