title: Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide.
abstract: We investigated the effects of bexarotene (a retinoid X receptor agonist), CD1530 (a retinoic acid receptor γ selective agonist), and the combination of these two drugs for the prevention of oral carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral-cavity and esophageal squamous-cell carcinoma previously generated in our laboratory. We observed decreased numbers of neoplastic tongue lesions and reduced lesion severity in the 4-NQO plus CD1530 (4N+C) and 4-NQO plus bexarotene plus CD1530 (4N+B+C) groups compared with the 4-NQO group. RNA-Seq analyses showed increases in transcripts in cell proliferation/cell cycle progression pathways in the 4-NQO vs. the untreated group. In addition, β-catenin and matrix metallopeptidase 9 (MMP9) protein levels and reactive oxygen species (ROS), as assessed by 4-hydroxynonenal (4-HNE) staining, were elevated in tongue tissues 17 wk after the termination of the 4-NQO treatment. The 4N+B, 4N+C, and 4N+B+C groups showed dramatically lower levels of β-catenin, MMP9, and 4-HNE staining compared with the 4-NQO group. The major reduction in 4-HNE staining in the retinoid treatment groups suggests a novel mechanism of action, reduction of ROS, by which bexarotene and CD1530 inhibit carcinogenesis.
authors.affiliation: Department of Pharmacology.
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Tang
authors.affiliation: Department of Pharmacology.
authors.forename: Kwame
authors.initials: K
authors.lastname: Osei-Sarfo
authors.affiliation: Department of Pharmacology.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Urvalek
authors.affiliation: Genomics Resources Core Facility, and.
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Theresa
authors.initials: T
authors.lastname: Scognamiglio
authors.affiliation: Department of Pharmacology, ljgudas@med.cornell.edu.
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000737:chemistry*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry; D001565:Benzoates / Q000737:chemistry*; D000077610:Bexarotene; D063646:Carcinogenesis; D002273:Carcinogens / Q000737:chemistry; D002453:Cell Cycle; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D005260:Female; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D009284:Naphthols / Q000737:chemistry*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid / Q000819:agonists; D012176:Retinoids / Q000008:administration & dosage*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D014280:Triglycerides / Q000097:blood; D051176:beta Catenin / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
chemical_list: D015112:4-Nitroquinoline-1-oxide; D016588:Anticarcinogenic Agents; D001565:Benzoates; D000077610:Bexarotene; D002273:Carcinogens; D020780:Matrix Metalloproteinase 9; D009284:Naphthols; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D051176:beta Catenin; D000097768:Retinoic Acid Receptor gamma; C000591478:4-(6-hydroxy-7-tricyclo(3.3.1.13,7)dec-1-yl-2-naphthalenyl)benzoic acid; C495267:CTNNB1 protein, mouse; C501830:Mmp9 protein, mouse
keywords: cancer prevention; oral cancer; retinoic acid receptor gamma agonist; retinoid X receptor; tongue squamous cell carcinoma