Induction of apoptosis of human tumor cells by a 4,9-diazapyrenium derivative and its affects on topoisomerase-II action.

Abstract

BACKGROUND:

5,10-Diphenyl-4,9-dimethyl-4,9-diazapyrenium hydrogensulfate (FDAP) is a newly synthesized DNA intercalator with strong antiproliferative activity against various human tumor cells. In this study, FDAP's potential to induce apoptosis in human pancreatic (MIAPaCa-2) and colon (Caco-2) carcinoma cells and its effects on topoisomerase-II activity were investigated.

METHODS:

Cytotoxicity was analyzed using the MTT assay. Antiproliferative activity was measured using a radioactive precursor incorporation assay. DNA fragmentation was analyzed by agarose gel electrophoresis. Apoptosis was detected using annexin-V fluorescein. To screen the topoisomerase-II-targeted effects of FDAP, cell-free assays were used.

RESULTS:

FDAP at concentrations of 10 and 1 microM caused a strong cytotoxic effect on MIAPaCa-2 cells, but only a slight effect on WI38 cell viability. Inhibition of the DNA, RNA and protein synthesis of the treated tumor cells was dependent on cell type. The DNA of the treated MIAPaCa-2 cells was fragmented. Phosphatidylserine externalization was detected in both tumor cell lines investigated. FDAP caused generation of DNA strand breaks due to interaction with human topoisomerase-IIalpha.

CONCLUSION:

1 microM FDAP caused apoptotic cell death of treated tumor cells. FDAP stimulated topoisomerase-II-mediated DNA cleavage and could be considered a topoisomerase-II poison.

• Authors: S Marczi, Lj Glavas-Obrovac, I Karner
• Journal: Chemotherapy (Chemotherapy) Vol. 51 Issue 4 Pg. 217-22 (Jul 2005) ISSN: 0009-3157 [Print] Switzerland
• PMID: 16006768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2005 S. Karger AG, Basel.

Chemical References

• 5,10-diphenyl-4,9-dimethyl-4,9-diazapyrenium
• Quinolinium Compounds
• DNA Topoisomerases, Type II

Topics

• Apoptosis (drug effects)
• Caco-2 Cells
• DNA Damage
• DNA Topoisomerases, Type II (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Humans
• Pancreatic Neoplasms (pathology)
• Quinolinium Compounds (pharmacology)
• Tumor Cells, Cultured