title: Anti-cancer effect of thiacremonone through down regulation of peroxiredoxin 6.
abstract: Thiacremonone (2, 4-dihydroxy-2, 5-dimethyl-thiophene-3-one) is an antioxidant substance as a novel sulfur compound generated from High-Temperature-High-Pressure-treated garlic. Peroxiredoxin 6 (PRDX6) is a member of peroxidases, and has glutathione peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Several studies have demonstrated that PRDX6 stimulates lung cancer cell growth via an increase of glutathione peroxidase activity. A docking model study and pull down assay showed that thiacremonone completely fits on the active site (cys-47) of glutathione peroxidase of PRDX6 and interacts with PRDX6. Thus, we investigated whether thiacremonone inhibits cell growth by blocking glutathione peroxidase of PRDX6 in the human lung cancer cells, A549 and NCI-H460. Thiacremonone (0-50 μg/ml) inhibited lung cancer cell growth in a concentration dependent manner through induction of apoptotic cell death accompanied by induction of cleaved caspase-3, -8, -9, Bax, p21 and p53, but decrease of xIAP, cIAP and Bcl2 expression. Thiacremonone further inhibited glutathione peroxidase activity in lung cancer cells. However, the cell growth inhibitory effect of thiacremonone was not observed in the lung cancer cells transfected with mutant PRDX6 (C47S) and in the presence of dithiothreitol and glutathione. In an allograft in vivo model, thiacremonone (30 mg/kg) also inhibited tumor growth accompanied with the reduction of PRDX6 expression and glutathione peroxidase activity, but increased expression of cleaved caspase-3, -8, -9, Bax, p21 and p53. These data indicate that thiacremonone inhibits tumor growth via inhibition of glutathione peroxidase activity of PRDX6 through interaction. These data suggest that thiacremonone may have potentially beneficial effects in lung cancer.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Miran
authors.initials: M
authors.lastname: Jo
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Hyung-Mun
authors.initials: HM
authors.lastname: Yun
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Kyung-Ran
authors.initials: KR
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Dong Hun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Cho
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Hwan-Soo
authors.initials: HS
authors.lastname: Yoo
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
authors.affiliation: College of Agriculture, Life and Environments Science, Chungbuk National University, Chungbuk, Korea.
authors.forename: Heon Sang
authors.initials: HS
authors.lastname: Jeong
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Jung
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Bang Yeon
authors.initials: BY
authors.lastname: Hwang
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Mi Kyeong
authors.initials: MK
authors.lastname: Lee
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D064591:Allografts; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005737:Garlic / Q000737:chemistry; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D054465:Peroxiredoxin VI / Q000235:genetics* / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D010936:Plant Extracts; D013876:Thiophenes; C524083:thiacremonone; D054465:Peroxiredoxin VI