title: Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function.
abstract: Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a nonadipogenic PPARγ agonist and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of lung squamous cell carcinoma (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU), which is applied topically, reliably triggering the development of SCC within 24 to 26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol-treated group (P = 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol-treated group. P = 0.004). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1-S cell-cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol changed redox status in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent.
authors.affiliation: Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.affiliation: Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Komas
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.affiliation: Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.affiliation: Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Yian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin. myou@mcw.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: You
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects; D002273:Carcinogens / Q000737:chemistry; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D002330:Carmustine / Q000031:analogs & derivatives / Q000737:chemistry; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000255:Adenosine Triphosphate; D016588:Anticarcinogenic Agents; D001713:Biphenyl Compounds; D002273:Carcinogens; D002330:Carmustine; D053148:Caspase 3; D053179:Caspase 7; D049452:Green Fluorescent Proteins; D017705:Lignans; D017382:Reactive Oxygen Species; C572573:N-nitroso-tris-chloroethylurea; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols