title: Combretastatin A-4 and structurally related triazole analogues induce caspase-3 and reactive oxygen species-dependent cell death in PC12 cells.
abstract: Cancer cells are more sensitive to oxidative stress due to higher levels of reactive oxygen species. Therefore, the ability of anti-cancer agent combretastatin A-4 (CA-4) and triazole analogues to induce reactive oxygen species may be important for selectivity against cancer cells. The purpose of the present study was to investigate the structural requirements for reactive oxygen species production by CA-4 and the triazole analogues Ana-2, Ana-3 and Ana-4. Ana-2 and Ana-3 mimic the cis configuration in CA-4; Ana-3 lacks the phenolic hydroxyl group, while Ana-4 mimics a trans configuration. The rat pheochromocytoma cancer cell line PC12 was used as model system. CA-4 and Ana-2 were highly toxic; Ana-3 was less toxic, whereas Ana-4 was non-toxic. The probe dihydroethidium detected reactive oxygen species production from CA-4, Ana-2, and Ana-3. CA-4 and Ana-2 also induced oxidation of the reactive oxygen species probe dihydrorhodamine and activation of caspase-3. Thus, the phenolic hydroxyl group in CA-4 and Ana-2 was necessary for dihydrorhodamine oxidation, caspase-3 activation, and increased cytotoxicity.
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway. gulzeb.aziz@farmasi.uio.no
authors: Gulzeb
authors: G
authors: Aziz
authors: Kristin
authors: K
authors: Odlo
authors: Trond V
authors: TV
authors: Hansen
authors: Ragnhild E
authors: RE
authors: Paulsen
authors: Gro H
authors: GH
authors: Mathisen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001632:Bibenzyls / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D017382:Reactive Oxygen Species; D014230:Triazoles; C040105:combretastatin; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9