Dual inhibition of topoisomerase II and tubulin polymerization by azatoxin, a novel cytotoxic agent.

Abstract

Azatoxin (NSC 640737) is a synthetic molecule that was rationally designed as a topoisomerase II inhibitor (Leteurtre et al., Cancer Res 52: 4478-4483, 1992). The present study was undertaken in order to investigate the molecular pharmacology and the cytotoxic activity of azatoxin in human tumor cells. Alkaline elution experiments performed in HL-60 cells demonstrated that: (1) azatoxin induces DNA-protein cross-links and protein-linked DNA single- and double-strand breaks characteristics of topoisomerase II inhibition in HL-60 cells; and (2) the potency of azatoxin is comparable to that of etoposide (VP-16). Testing of azatoxin in 45 human cell lines in the National Cancer Institute (NCI) in vitro Drug Screening Program indicated that azatoxin was potent (mean IC50 = 0.13 microM), but that its cell line sensitivity profile was correlated with that of tubule inhibitors rather than that of topoisomerase II inhibitors. These data led us to investigate the anti-tubulin activity of azatoxin. We found that azatoxin inhibited tubulin polymerization in vitro and was a mitotic inhibitor at 1 microM and above in the human colon cancer cell line KM20L2. In these cells topoisomerase II inhibition, as detected by the induction of protein-linked DNA strand breaks, required azatoxin concentrations of at least 10 microM. In summary, azatoxin is a potent cytotoxic agent that inhibited both tubulin and topoisomerase II. At lower azatoxin concentrations the former activity prevailed whereas at higher concentrations topoisomerase II inhibition became prominent.

• Authors: E Solary, F Leteurtre, K D Paull, D Scudiero, E Hamel, Y Pommier
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 45 Issue 12 Pg. 2449-56 (Jun 22 1993) ISSN: 0006-2952 [Print] England
• PMID: 8392342 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Indoles
• Topoisomerase II Inhibitors
• Tubulin
• Tubulin Modulators
• azatoxin
• Etoposide

Topics

• Cell Death (drug effects)
• Cell Division (drug effects)
• Cell Line (drug effects)
• DNA Damage
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Etoposide (pharmacology)
• Humans
• Indoles (pharmacology)
• Mitosis (drug effects)
• Topoisomerase II Inhibitors
• Tubulin (chemistry)
• Tubulin Modulators
• Tumor Cells, Cultured (drug effects)