Title | Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Tang X-H, Osei-Sarfo K, Urvalek AM, Zhang T, Scognamiglio T, Gudas LJ |
Journal | Proc Natl Acad Sci U S A |
Volume | 111 |
Issue | 24 |
Pagination | 8907-12 |
Date Published | 2014 Jun 17 |
ISSN | 1091-6490 |
Keywords | 4-Nitroquinoline-1-oxide, Animals, Anticarcinogenic Agents, Benzoates, beta Catenin, Bexarotene, Carcinogenesis, Carcinogens, Cell Cycle, Cell Proliferation, Drug Screening Assays, Antitumor, Drug Synergism, Esophageal Neoplasms, Female, Matrix Metalloproteinase 9, Mice, Mice, Inbred C57BL, Mouth Neoplasms, Naphthols, Oxidative Stress, Reactive Oxygen Species, Receptors, Retinoic Acid, Retinoids, Tetrahydronaphthalenes, Triglycerides |
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. |
DOI | 10.1073/pnas.1404828111 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 24927566 |
PubMed Central ID | PMC4066471 |
Grant List | R01-AA018332 / AA / NIAAA NIH HHS / United States T32 CA062948 / CA / NCI NIH HHS / United States T32-CA062948 / CA / NCI NIH HHS / United States R01 AA018332 / AA / NIAAA NIH HHS / United States R01-DE010389 / DE / NIDCR NIH HHS / United States F32-AA021045 / AA / NIAAA NIH HHS / United States F32 AA021045 / AA / NIAAA NIH HHS / United States R01 DE010389 / DE / NIDCR NIH HHS / United States |