title: Targeting the insulin-like growth factor-1 receptor by picropodophyllin for lung cancer chemoprevention.
abstract: Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane heterotetramer that is activated by Insulin-like growth factor 1 and is crucial for tumor transformation and survival of malignant cells. Importantly, IGF-1R overexpression has been reported in many different cancers, implicating this receptor as a potential target for anticancer therapy. Picropodophyllin (PPP) is a potent inhibitor of IGF-1R and has antitumor efficacy in several cancer types. However, the chemopreventive effect of PPP in lung tumorigenesis has not been investigated. In this study, we investigated the chemopreventive activity of PPP in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and PPP was given by nasal inhalation to female A/J mice. Lung tumorigenesis was assessed by tumor multiplicity and tumor load. PPP significantly decreased tumor multiplicity and tumor load. Tumor multiplicity and load were decreased by 52% and 78% respectively by 4 mg/ml aerosolized PPP. Pharmacokinetics analysis showed good bioavailability of PPP in lung and plasma. Treatment with PPP increased staining for cleaved caspase-3 and decreased Ki-67 in lung tumors, suggesting that the lung tumor inhibitory effects of PPP were partially through inhibition of proliferation and induction of apoptosis. In human lung cancer cell lines, PPP inhibited cell proliferation, and also inhibited phosphorylation of IGF-1R downstream targets, AKT and MAPK, ultimately resulting in increased apoptosis. PPP also reduced cell invasion in lung cancer cell lines. In view of our data, PPP merits further investigation as a promising chemopreventive agent for human lung cancer.
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: Jing
authors.initials: J
authors.lastname: Pan
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.
authors.forename: Ming
authors.initials: M
authors.lastname: You
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000187:drug effects*
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; C415032:picropodophyllin; D001564:Benzo(a)pyrene; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin
keywords: IGF-1R; aerosol; apoptosis; benzo(a)pyrene; chemoprevention; mouse lung tumorigenesis; picropodophyllin (PPP)