Compound 968 reverses adriamycin resistance in breast cancer MCF-7ADR cells via inhibiting P-glycoprotein function independently of glutaminase

Adriamycin (ADR) is a chemotherapeutic drug widely utilized to treat multiple types of cancers; however, the clinical efficacy of ADR is compromised due to the development of drug resistance in patients. The combination of drugs with ADR may provide a better therapeutic regimen to overcome this obst...

Full description

Saved in:
Bibliographic Details
Published in:Cell death discovery 2021-08, Vol.7 (1), p.204-204, Article 204
Main Authors: Yang, Ronghui, Guo, Zihao, Zhao, Yiliang, Ma, Lingdi, Li, Binghui, Yang, Chuanzhen
Format: Article
Language:English
Subjects:
631/154/555
631/67/1347
Apoptosis
Biochemistry
Biomedical and Life Sciences
Biotin
Breast cancer
Cell Biology
Cell Cycle Analysis
Cell death
Cell viability
Chemotherapy
Drug development
Drug resistance
Glutaminase
Glycoproteins
Immunoprecipitation
Life Sciences
P-Glycoprotein
Stem Cells
Streptavidin
Tumor cells
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Adriamycin (ADR) is a chemotherapeutic drug widely utilized to treat multiple types of cancers; however, the clinical efficacy of ADR is compromised due to the development of drug resistance in patients. The combination of drugs with ADR may provide a better therapeutic regimen to overcome this obstacle. Glutaminase (GLS) has been explored as a therapeutic cancer target, and its inhibition also results in increased sensitivity of tumor cells to chemotherapeutic agents. This study aimed to investigate whether GLS inhibition could reverse ADR resistance. We treated the ADR-resistant MCF-7 (MCF-7 ADR ) cells with a GLS inhibitor, compound 968 or CB-839, in combination with ADR. We found that compound 968, rather than CB-839, together with ADR synergistically inhibited the cell viability. These results indicated that compound 968 reversed ADR resistance in MCF-7 ADR cells independently of GLS. Moreover, we modified the structure of compound 968 and finally obtained a compound 968 derivative, SY-1320, which was more potent than compound 968 in eliminating the drug resistance in MCF-7 ADR cells. Furthermore, using drug affinity responsive target stability and streptavidin–biotin immunoprecipitation assays, we demonstrated that SY-1320 could specifically target P-glycoprotein (P-gp) and increase ADR accumulation through inhibition of P-gp, thereby resulting in cell death in MCF-7 ADR cells. Together, our findings indicate that compound 968 or SY-1320 might be a promising drug for new combination chemotherapy in breast cancer to overcome the drug resistance.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-021-00590-1