Adva-27a, a novel podophyllotoxin derivative found to be effective against multidrug resistant human cancer cells

Abderrazzak Merzouki, Michael D. Buschmann, Myriam Jean, Rebecca S. Young, Si Liao, Susannah Gal, Zuomei Li, Steve N. Slilaty

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Background/Aim: Multidrug resistance poses a serious challenge in cancer therapy. To address this problem, we designed and synthesized Adva-27a, a novel non-ester GEM-difluorinated C-glycoside derivative of podophyllotoxin. Materials and Methods: Adva-27a activity was evaluated in a variety of assays including inhibition of topoisomerase IIα, cytotoxic activity in drug-sensitive and drug-resistant cancer cell lines, metabolic stability in human liver microsomes and pharmacokinetic properties in rats. Results: Adva-27a exhibited dose-dependent human topoisomerase IIα inhibitory activity and dose-dependent growth inhibitory activity in several drug-sensitive and two multidrug-resistant cancer cell lines. In the multidrug-resistant cell lines, MCF-7/MDR (breast cancer) and H69AR (small-cell lung cancer), Adva-27a was significantly more potent than etoposide. The metabolic stability of Adva-27a in human liver microsomes and its pharmacokinetic properties in rats were better than those of etoposide. Conclusion: Our studies have identified Adva-27a as a novel topoisomerase II inhibitor with superior cytotoxic activity against multidrug-resistant human cancer cells and more desirable pharmacokinetic properties than etoposide.

Original languageEnglish (US)
Pages (from-to)4423-4432
Number of pages10
JournalAnticancer Research
Volume32
Issue number10
StatePublished - Oct 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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