Semi-Synthetic Dihydrotestosterone Derivatives Modulate Inherent Multidrug Resistance and Sensitize Colon Cancer Cells to Chemotherapy.
Pharmaceutics
; 15(2)2023 Feb 09.
Article
em En
| MEDLINE
| ID: mdl-36839907
ABSTRACT
Multidrug resistance (MDR) is a serious hurdle to successful cancer therapy. Here, we examined the efficiency of novel semi-synthetic dihydrotestosterone derivatives, more specifically androstano-arylpyrimidines in inhibiting the efflux activity of ATP-binding cassette (ABC) transporters and sensitizing inherently MDR colon cancer cells to various chemotherapy drugs. Using the Rhodamine123 accumulation assay, we evaluated the efflux activity of cancer cells following treatments with androstano-arylpyrimidines. We found that acetylated compounds were capable of attenuating the membrane efflux of inherently MDR cells; however, deacetylated counterparts were ineffective. To delineate the possible molecular mechanisms underlying these unique activities of androstano-arylpyrimidines, the degree of apoptosis induction was assessed by AnnexinV-based assays, both upon the individual as well as by steroid and chemotherapy agent combination treatments. Five dihydrotestosterone derivatives applied in combination with Doxorubicin or Epirubicin triggered massive apoptosis in MDR cells, and these combinations were more efficient than chemotherapy drugs together with Verapamil. Furthermore, our results revealed that androstano-arylpyrimidines induced significant endoplasmic reticulum stress (ER stress) but did not notably modulate ABC transporter expression. Therefore, ER stress triggered by acetylated androstano-arylpyrimidines is probably involved in the mechanism of efflux pump inhibition and drug sensitization which can be targeted in future drug developments to defeat inherently multidrug-resistant cancer.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Pharmaceutics
Ano de publicação:
2023
Tipo de documento:
Article