Caspase-dependent cell death mediates potent cytotoxicity of sulfide derivatives of 9-anilinoacridine.

Abstract

9-anilinoacridine contains a tricyclic and planar aromatic structure that enables DNA intercalation and inhibition of topoisomerase II. Two recently developed sulfide derivatives of 9-anilinoacridines, 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) and 3-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(3-hydroxypropyl)amino)propan-1-ol (CK0403), displayed potent cytotoxic activity in multiple cancer cell lines. In-vitro enzymatic assay demonstrated that CK0402 and CK0403 directly inhibit decatenation reaction of topoisomerase IIalpha. Cells exposed to CK0403 showed DNA fragmentation, and activation of caspase-3 and caspase-2, indicating that it triggers caspase-dependent apoptosis. This was further supported by the fact that cytotoxicity of these drugs is attenuated by pharmacological inhibition of caspases with z-VAD-FMK. Studies with wild-type and p53 primary mouse embryonic fibroblasts demonstrated that p53 does not play a significant role in cell death process initiated by this kind of drug. In addition, pharmacological inhibition of poly(ADP-ribose) polymerase-1activity moderately enhanced cytotoxic activity of sulfide 9-anilinoacridine, suggesting that poly(ADP-ribose) polymerase-1 may have a protective function against 9-anilinoacridine-induced cell death process.

• Authors: Sang-ki Park, Hyerim Kang, Chul-Hoon Kwon
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 19 Issue 4 Pg. 381-9 (Apr 2008) ISSN: 0959-4973 [Print] England
• PMID: 18454048 (Publication Type: Journal Article)

Chemical References

• 2-((4-(4-(acridin-9-ylamino)phenylthio)phenyl)(2-hydroxyethyl)amino)ethan-1-ol
• 3-((4-(4-(acridin-9-ylamino)phenylthio)phenyl)(3-hydroxypropyl)amino)propan-1-ol
• Acridines
• Antineoplastic Agents
• Poly(ADP-ribose) Polymerase Inhibitors
• Reactive Oxygen Species
• Sulfides
• Topoisomerase II Inhibitors
• Tumor Suppressor Protein p53
• Poly(ADP-ribose) Polymerases
• Caspases
• DNA Topoisomerases, Type II

Topics

• Acridines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Blotting, Western
• Caspases (physiology)
• Cell Line, Transformed
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA Fragmentation (drug effects)
• DNA Topoisomerases, Type II (metabolism)
• Fibroblasts (cytology, drug effects, metabolism)
• Humans
• Mice
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Reactive Oxygen Species (metabolism)
• Sulfides (pharmacology)
• Topoisomerase II Inhibitors
• Tumor Suppressor Protein p53 (genetics, physiology)