title: Pioglitazone prevents smoking carcinogen-induced lung tumor development in mice.
abstract: Pioglitazone (PGZ), a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligand, is known to have anti-tumor activity by inducing tumor cell apoptosis. However, it is unknown whether it can be used to prevent smoking carcinogen-induced lung tumor development. We induced mouse lung tumors using smoking carcinogen 4- methylnitrosamino-l-3-pyridyl-butanone (NNK). PGZ was given at two early stages before the tumor formation. The role and the functional mechanism of PGZ were investigated in the development of mouse pulmonary tumors. The tumor development was monitored and PPARγ activity and endogenous PPARγ ligands 15(S)-HETE, 13(S)-HODE were determined. The application of PGZ before alveolar hyperplasia formation (Group NPa) and at the early phase of alveolar hyperplasia formation (Group NPb) significantly prevented the lung tumor development especially in Group NPb mice (all p < 0.05). PGZ not only prevented the NNK-mediated reduction of endogenous ligands 15(S)-HETE and 13(S)-HODE, but also increased 13(S)-HODE level in Group NPb mice. PPARγ transcriptional activity was increased in NNKstimulated lung tissues when PGZ was given. The in vivo results were confirmed in the human lung cancer cells, which showed that PGZ induced lung cancer cell apoptosis through up-regulating nuclear PPARγ expression, inducing PPARγ transcriptional activity and increasing the levels of PPARγ ligands in NNK-treated cells. The early application of PGZ is able to prevent NNK-induced lung tumor development through maintaining the level of endogenous PPARγ ligands 15(S)-HETE and 13(S)-HODE and activation of PPARγ.
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Li
authors.forename: A W Y
authors.initials: AW
authors.lastname: Kong
authors.forename: H
authors.initials: H
authors.lastname: Yuan
authors.forename: L T
authors.initials: LT
authors.lastname: Ma
authors.forename: M K Y
authors.initials: MK
authors.lastname: Hsin
authors.forename: I Y P
authors.initials: IY
authors.lastname: Wan
authors.forename: M J
authors.initials: MJ
authors.lastname: Underwood
authors.forename: G G
authors.initials: GG
authors.lastname: Chen
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006965:Hyperplasia; D008024:Ligands; D008041:Linoleic Acids / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009602:Nitrosamines; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000009:adverse effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D006893:Hydroxyeicosatetraenoic Acids; D008024:Ligands; D008041:Linoleic Acids; D009602:Nitrosamines; D047495:PPAR gamma; D045162:Thiazolidinediones; C024348:13-hydroxy-9,11-octadecadienoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000077205:Pioglitazone