Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-06, Vol.111 (24), p.8907-8912
Main Authors: Tang, Xiao-Han, Osei-Sarfo, Kwame, Urvalek, Alison M., Zhang, Tuo, Scognamiglio, Theresa, Gudas, Lorraine J.
Format: Article
Language:English
Subjects:
4-Nitroquinoline-1-oxide - chemistry
Agonists
Animals
Anticarcinogenic Agents - chemistry
Benzoates - chemistry
beta Catenin - metabolism
Bexarotene
Biological Sciences
Cancer
Carcinogenesis
Carcinogens
Carcinogens - chemistry
Cell Cycle
Cell Proliferation
Disease prevention
Drug Screening Assays, Antitumor
Drug Synergism
Drug use
Esophageal cancer
Esophageal Neoplasms - chemically induced
Esophageal Neoplasms - drug therapy
Esophageal Neoplasms - prevention & control
Female
Genes
Lesions
Matrix Metalloproteinase 9 - metabolism
Mice
Mice, Inbred C57BL
Mouth neoplasms
Mouth Neoplasms - chemically induced
Mouth Neoplasms - drug therapy
Mouth Neoplasms - prevention & control
Naphthols - chemistry
Oncology
Oxidative Stress
Reactive Oxygen Species
Receptors, Retinoic Acid - agonists
Retinoic Acid Receptor gamma
Retinoids
Retinoids - administration & dosage
Rodents
Squamous cell carcinoma
Tetrahydronaphthalenes - administration & dosage
Triglycerides - blood
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1404828111