title: Generation of reactive oxygen species by polyenylpyrroles derivatives causes DNA damage leading to G2/M arrest and apoptosis in human oral squamous cell carcinoma cells.
abstract: Oral squamous cell carcinoma (OSCC) accounts for 5.8% of all malignancies in Taiwan and the incidence of OSCC is on the rise. OSCC is also a common malignancy worldwide and the five-year survival rate remains poor. Therefore, new and effective treatments are needed to control OSCC. In the present study we have investigated the efficacy and associated mechanisms of polyenylpyrroles and their analogs in both in vitro cell culture and in vivo nude mice xenografts. Auxarconjugatin B (compound 1a) resulted in cell cycle arrest in the G2/M phase and caspase-dependent apoptosis in OEC-M1 and HSC-3 cells by activating DNA damage and mitochondria dysfunction through the loss of mitochondrial membrane potential, release of cytochrome c, increase in B-cell lymphoma-2-associated X protein level, and decrease in B-cell lymphoma-2 level. Compound 1a-induced generation of intracellular reactive oxygen species through cytochrome P450 1A1 was identified as a major mechanism of its effect for DNA damage, mitochondria dysfunction and apoptosis, which was reversed by antioxidant N-acetylcysteine as well as cytochrome P450 1A1 inhibitor and specific siRNA. Furthermore, compound 1a-treated nude mice showed a reduction in the OEC-M1 xenograft tumor growth and an increase in the caspase-3 activation in xenograft tissue. These results provide promising insights as to how compound 1a mediates cytotoxicity and may prove to be a molecular rationale for its translation into a potential therapeutic against OSCC.
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan. kfhua@niu.edu.tw
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Liao
authors.forename: Zhanxiong
authors.initials: Z
authors.lastname: Fang
authors.forename: Feng-Ling
authors.initials: FL
authors.lastname: Yang
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Yang
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chen
authors.forename: Yi-Chich
authors.initials: YC
authors.lastname: Chiu
authors.forename: May-Lan
authors.initials: ML
authors.lastname: Liu
authors.forename: Yulin
authors.initials: Y
authors.lastname: Lam
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013624:Taiwan
chemical_list: D000970:Antineoplastic Agents; D011753:Pyrones; D011758:Pyrroles; D017382:Reactive Oxygen Species; C514631:auxarconjugatin A; D045304:Cytochromes c; D053148:Caspase 3