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Overcoming methotrexate resistance in breast cancer tumour cells by the use of a new cell-penetrating peptide
- Source :
- Biochemical pharmacology. 71(4)
- Publication Year :
- 2005
-
Abstract
- Resistance to chemotherapy limits the effectiveness of anti-cancer drug treatment. Here, we present a new approach to overcome the setback of drug resistance by designing a conjugate of a cell-penetrating peptide and the cytostatic agent methotrexate (MTX). Two different peptides, YTA2 and YTA4, were designed and their intracellular delivery efficiency was characterized by fluorescence microscopy and quantified by fluorometry. MTX was conjugated to the transport peptides and the ability of the peptide-MTX conjugates to inhibit dihydrofolate reductase, the target enzyme of MTX, was found to be 15 and 20 times less potent than MTX. In addition, in vitro studies were performed in a drug resistant cell model using the 100-fold MTX resistant breast cancer cells MDA-MB-231. At a concentration of 1 microM, the peptide-MTX conjugates were shown to overcome MTX resistance and kill the cells more efficiently than MTX alone. Estimated EC50's were determined for MTX, MTX-YTA2 and YTA2 to be 18.5, 3.8 and 20 microM, respectively. In summary, cell-penetrating peptide conjugation of MTX is a new way of increasing delivery, and thereby, the potency of already well-characterized therapeutic molecules into drug resistant tumour cells.
- Subjects :
- musculoskeletal diseases
Antimetabolites, Antineoplastic
medicine.drug_class
Cell Survival
Breast Neoplasms
Drug resistance
Pharmacology
Biochemistry
Antimetabolite
Mass Spectrometry
chemistry.chemical_compound
immune system diseases
Cell Line, Tumor
Dihydrofolate reductase
medicine
Humans
heterocyclic compounds
Fluorometry
skin and connective tissue diseases
biology
Dose-Response Relationship, Drug
L-Lactate Dehydrogenase
business.industry
In vitro
Protein Transport
Tetrahydrofolate Dehydrogenase
Methotrexate
chemistry
Microscopy, Fluorescence
Doxorubicin
Drug Resistance, Neoplasm
Drug delivery
Antifolate
biology.protein
Cell-penetrating peptide
business
Peptides
Oligopeptides
medicine.drug
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 71
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Biochemical pharmacology
- Accession number :
- edsair.doi.dedup.....56f9b6ad2db9392742f196fdf129e8de