title: A phenolic acid phenethyl urea derivative protects against irradiation-induced osteoblast damage by modulating intracellular redox state.
abstract: Because irradiation may cause osteoradionecrosis, antioxidant supplementation is often used to suppress irradiation-mediated injury. This study examined whether a synthetic phenethyl urea compound, (E)-1-(3,4-dihydroxyphenethyl)-3-(3,4-dihydroxystyryl)urea (DPDS-U), prevents irradiation-mediated cellular damage in MC3T3-E1 osteoblastic cells. A relatively high dose of irradiation (>4 Gy) decreased cell viability and proliferation and induced DNA damage and cell cycle arrest at the G(2)/M phase with the attendant increase of cyclin B1. Irradiation with 8 Gy induced intracellular reactive oxygen species (ROS) production and lipid peroxidation, and reduced glutathione content and superoxide dismutase activity in the cells. These events were significantly suppressed by treatment with 200 µM DPDS-U or 5 mM N-acetyl cysteine (NAC). DPDS-U or irradiation alone significantly increased heme oxygenase-1 (HO-1) expression and nuclear factor E2 p45-related factor-2 (Nrf2) nuclear translocation. Interestingly, pretreatment with DPDS-U facilitated irradiation-induced activation of the Nrf2/HO-1 pathway. The potential of DPDS-U to mediate HO-1 induction and protect against irradiation-mediated cellular damage was almost completely attenuated by transient transfection with Nrf2-specific siRNA or treatment with a pharmacological HO-1 inhibitor, zinc protoporphyrin IX. Additional experiments revealed that DPDS-U induced a radioprotective mechanism that differs from that induced by NAC through activation of Nrf2/HO-1 signaling. Collectively, our data suggest that DPDS-U-induced radioprotection is due to its dual function as an antioxidant to remove directly excessive intracellular ROS and as a prooxidant to stimulate intracellular redox-sensitive survival signal.
authors.affiliation: Department of Oral and Maxillofacial Radiology and Research Institute of Clinical Medicine, Chonbuk National University, Jeonju, 561-756, South Korea.
authors.forename: Kyoung A
authors.initials: KA
authors.lastname: Kim
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kook
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Song
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013343:Styrenes / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C548394:(E)-1-(3,4-dihydroxyphenethyl)-3-styrylurea; C550461:1-(3,4-dihydroxystyryl)-3-(4-hydroxyphenethyl)urea; D000975:Antioxidants; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D013343:Styrenes; D014508:Urea; D000111:Acetylcysteine
keywords: ANTIOXIDANT; HEME OXYGENASE-1; IRRADIATION; NUCLEAR FACTOR E2 P45-RELATED FACTOR 2; OXIDATIVE STRESS