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

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.

• Authors: Abderrazzak Merzouki, Michael D Buschmann, Myriam Jean, Rebecca S Young, Si Liao, Susannah Gal, Zuomei Li, Steve N Slilaty
• Journal: Anticancer research (Anticancer Res) Vol. 32 Issue 10 Pg. 4423-32 (Oct 2012) ISSN: 1791-7530 [Electronic] Greece
• PMID: 23060568 (Publication Type: Journal Article)

Chemical References

• Adva-27a podophyllotoxin
• Antineoplastic Agents
• C-glycoside
• Fluorine Compounds
• Glycosides
• Monosaccharides
• Topoisomerase II Inhibitors
• Etoposide
• Podophyllotoxin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, enzymology)
• Cell Line, Tumor
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Etoposide (pharmacology)
• Female
• Fluorine Compounds (chemical synthesis, pharmacology)
• Glycosides
• Humans
• Male
• Microsomes, Liver (metabolism)
• Monosaccharides (chemistry, pharmacology)
• Podophyllotoxin (analogs & derivatives, chemical synthesis, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Small Cell Lung Carcinoma (drug therapy, enzymology)
• Topoisomerase II Inhibitors (pharmacology)