Caspase-dependent cell death mediates potent cytotoxicity of sulfide derivatives of 9-anilinoacridine.
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.
Park
Sang-ki
SK
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John's University, Queens, New York 11439, USA. parks@stjohns.edu
Kang
Hyerim
H
Kwon
Chul-Hoon
CH
D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
C530271:2-((4-(4-(acridin-9-ylamino)phenylthio)phenyl)(2-hydroxyethyl)amino)ethan-1-ol; C530272:3-((4-(4-(acridin-9-ylamino)phenylthio)phenyl)(3-hydroxypropyl)amino)propan-1-ol; D000166:Acridines; D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D013440:Sulfides; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D004250:DNA Topoisomerases, Type II