Backstabbing P-gp: Side-chain cleaved ecdysteroid 2,3-dioxolanes hyper-sensitize MDR cancer cells to doxorubicin without efflux inhibition

Attila Hunyadi, József Csábi, Ana Martins, Joseph Molnár, Attila Balázs, Gábor Tóth

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds' effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer.

Original languageEnglish
Article number199
JournalMolecules
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

  • ABCB1 efflux transporter
  • Cancer
  • Chemo-sensitization
  • Combination therapy
  • Ecdysteroid metabolite
  • Multi-drug resistance
  • Poststerone acetonide

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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