New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics

The inhibition of the Mdm2-p53 protein-protein interaction is a promising strategy for anticancer therapy. However, the problem of developing secondary chemoresistance in tumors treated with such drugs has not yet been sufficiently studied. In this work, we compared the properties of a drug-resistan...

Full description

Saved in:
Bibliographic Details
Published inBiomedicines Vol. 12; no. 3; p. 547
Main Authors Grigoreva, Tatyana, Sagaidak, Aleksandra, Novikova, Daria, Tribulovich, Vyacheslav
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 29.02.2024
MDPI
Subjects
Antimitotic agents
Antineoplastic agents
Biotechnology industry
Cancer
Care and treatment
Cell cycle
Chemoresistance
Chemotherapy
cytostatics
Cytotoxicity
Development and progression
Drug resistance
Drug therapy
Drugs
Glycoproteins
MDM2 protein
MDR
Medical research
Mutation
Nutlin-3a
P-glycoprotein
p53 Protein
Paclitaxel
Proteins
Reagents
Statistical analysis
Tumor cells
Tumor proteins
Russia
United States > US
BCRP
P-glycoprotein
paclitaxel
MDR
drug resistance
Nutlin-3a
cytostatics
Online AccessGet full text

Cover

More Information
Summary:The inhibition of the Mdm2-p53 protein-protein interaction is a promising strategy for anticancer therapy. However, the problem of developing secondary chemoresistance in tumors treated with such drugs has not yet been sufficiently studied. In this work, we compared the properties of a drug-resistant cell line obtained during long-term cultivation in the presence of an Mdm2 inhibitor, Nutlin-3a, with a similarly obtained line insensitive to the cytostatic drug paclitaxel. We first confirmed the higher safety levels of Mdm2 inhibitors when compared with cytostatics in terms of the development of secondary chemoresistance. We showed that Nutlin-3a affects both the targeted p53-mediated cellular machinery and the universal ABC-mediated efflux mechanism. While both targeted and general defense mechanisms are activated by the Mdm2 inhibitor, it still increases the susceptibility of tumor cells to other drugs. The results obtained indicate that the risks of developing chemoresistance under the therapy with a targeted agent are fundamentally lower than during cytotoxic therapy.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines12030547