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

Xiao-Han Tang; Kwame Osei-Sarfo; Alison M. Urvalek; Tuo Zhang; Theresa Scognamiglio; Lorraine J. Gudas

doi:10.1073/pnas.1404828111

Edited by Gregg L. Semenza, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 12, 2014 (received for review March 14, 2014)

Significance

Oral-cavity squamous-cell carcinoma is one of the most common human cancers in the world. About 60–70% of oral-cavity carcinoma cases are diagnosed only after the tumors have become locally advanced. Therefore, in addition to treatment, prevention of oral cancer is a very important goal. In this study, we found that the combination of the drugs bexarotene and CD1530 was more effective than either drug alone in preventing oral carcinogenesis in our mouse model of human oral and esophageal cancers. We envision that the combination of bexarotene and CD1530 could potentially be applied to humans at a high risk for oral cancer, as a very effective strategy for the prevention and treatment of human oral cancer.

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.

Footnotes

↵¹K.O.-S. and A.M.U. contributed equally to this work.
↵²To whom correspondence should be addressed. E-mail: ljgudas{at}med.cornell.edu.

Author contributions: X.-H.T. and L.J.G. designed research; X.-H.T., K.O.-S., and A.M.U. performed research; X.-H.T. contributed new reagents/analytic tools; X.-H.T., T.Z., and T.S. analyzed data; and X.-H.T. and L.J.G. wrote the paper.
Conflict of interest statement: A patent for the use of this combination of bexarotene and CD1530 has been filed by Weill Cornell Medical College.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE54246).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1404828111/-/DCSupplemental.