title: The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice.
abstract: LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1β, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology.
authors.affiliation: Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, New Hampshire.
authors.forename: Martine
authors.initials: M
authors.lastname: Cao
authors.affiliation: Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, New Hampshire.
authors.forename: Darlene B
authors.initials: DB
authors.lastname: Royce
authors.affiliation: Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, New Hampshire.
authors.forename: Renee
authors.initials: R
authors.lastname: Risingsong
authors.affiliation: Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, New Hampshire.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.affiliation: Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, New Hampshire.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.affiliation: Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, New Hampshire. Michigan State University, Department of Pharmacology and Toxicology, East Lansing, Michigan. liby.kare@msu.edu.
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage; D063646:Carcinogenesis; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007249:Inflammation; D008070:Lipopolysaccharides / Q000737:chemistry; D008074:Lipoproteins / Q000097:blood; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009539:Nicotinic Acids / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000008:administration & dosage; D010647:Phenyl Ethers / Q000494:pharmacology*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D020298:U937 Cells; D000077337:Vorinostat
chemical_list: C508470:7-(2-(2,2-difluoroethoxy)-3,5-di-tert-butylbenzene)-3-methylocta-2,4,6-trienoic acid; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; D005231:Fatty Acids, Unsaturated; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D008074:Lipoproteins; D009539:Nicotinic Acids; D010647:Phenyl Ethers; D013764:Tetrahydronaphthalenes; D009569:Nitric Oxide; D000077337:Vorinostat; D016190:Carboplatin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D017239:Paclitaxel; C095104:LG 100268