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Reactive oxygen species up‐regulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin
Author(s) -
Lee DaeHee,
Rhee Juong G,
Lee Yong J
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00245.x
Subject(s) - wogonin , apoptosis , reactive oxygen species , comet assay , programmed cell death , puma , scutellaria baicalensis , dna damage , cytotoxicity , chemistry , cancer cell , cancer research , pharmacology , biology , cancer , medicine , biochemistry , in vitro , dna , pathology , genetics , alternative medicine , traditional chinese medicine
Background and purpose: Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) triggers apoptotic death in a variety of cancer cells without marked toxicity to most normal cells. We previously reported that wogonin, a potent anticancer agent from a Chinese herb, up‐regulates p53 in prostate cancer cells. In this study, the effects of combinations of TRAIL and wogonin on a human prostate cancer cell line LNCaP, resistant to TRAIL, was evaluated for evidence of synergy in triggering apoptosis. Experimental approach: Western blot assay and the ‘comet’ assay were used to study the underlying mechanisms of cell death and search for any mechanisms of enhancement of TRAIL‐induced apoptosis in the presence of wogonin. Key results: During combined treatment with wogonin and TRAIL, cytotoxicity, poly(ADP‐ribose) polymerase cleavage and caspase activation were associated with up‐regulation of p53 through DNA damage and reactive oxygen species (ROS) generation. N‐acetylcysteine (NAC), an antioxidant, inhibited ROS generation and synergistic interaction between TRAIL and wogonin. Experimental results in human colon cancer HCT116 cells demonstrated that p53‐dependent Puma up‐regulation played an important role; deficiency in either p53 or Puma prevented wogonin‐enhanced TRAIL‐induced apoptosis. Conclusions and implications: The present studies suggest that wogonin enhances TRAIL‐induced cytotoxicity through up‐regulation of p53 and Puma, mediated by ROS.