This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chun, K.-H. Articles by Lotan, R. Search for Related Content PubMed PubMed Citation Articles by Chun, K.-H. Articles by Lotan, R.

The Synthetic Heteroarotinoid SHetA2 Induces Apoptosis in Squamous Carcinoma Cells through a Receptor-independent and Mitochondria-dependent Pathway¹

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [K-H. C., W. K. H., R. L.]; Department of Obstetrics and Gynecology, and Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190 [D. M. B.]; and The Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078 [K. D. B.]

Retinoids that regulate cell growth, differentiation, and apoptosis have shown promising results in preclinical studies and in a few clinical trials of cancer chemoprevention and therapy. However, the clinical use of retinoids is limited by resistance of certain malignant cells to their antitumor effects and by side effects. To identify more potent retinoids, we examined the effects of heteroarotinoids (Hets), new synthetic retinoids with reduced toxicity, on the growth of human head and neck squamous cell carcinoma (HNSCC) lines. Six Hets with different retinoic acid receptor activation potentials were found to exhibit distinct efficacies. The most potent among the Hets examined, SHetA2, {[(4-nitrophenyl)amino][2,2,4,4-tetramethyl thiochroman-6-yl)amino] methane-1-thione}, was more effective than either all-trans- or 9-cis-RA. The growth of UMSCC38, the most sensitive among the eight HNSCC cell lines examined, was suppressed by ShetA2 in a dose- and time-dependent fashion. SHetA2-induced apoptosis in UMSCC38 cells was comparable with N-(4-hydroxyphenyl)retinamide (4HPR). Reactive oxygen species (ROS) generation in the UMSCC38 cells was increased by SHetA2, and this effect was suppressed by the antioxidant butylated hydroxyanisol, which also suppressed SHetA2-induced apoptosis. SHetA2 suppressed mitochondrial permeability transition and enhanced cytochrome c release from mitochondria. Both of these effects were prevented by cyclosporin A, which also decreased SHetA2-induced apoptosis. SHetA2 increased caspase-3-like activity, and a caspase-3 inhibitor diminished SHetA2-induced apoptosis. Several retinoid receptor antagonists failed to prevent apoptosis induction by SHetA2. These results demonstrate that SHetA2 is a potent, receptor-independent, apoptosis inducer that acts on the mitochondria in HNSCC cells. Further investigation of the potential of SHetA2 in prevention and therapy of HNSCC is warranted also because of much lower toxicities compared with receptor active retinoids.

This article has been cited by other articles:

				T. Liu, C. P. Masamha, S. Chengedza, K. D. Berlin, S. Lightfoot, F. He, and D. M. Benbrook Development of flexible-heteroarotinoids for kidney cancer Mol. Cancer Ther., May 1, 2009; 8(5): 1227 - 1238. [Abstract] [Full Text] [PDF]

				Y. Lin, X. Liu, P. Yue, D. M. Benbrook, K. D. Berlin, F. R. Khuri, and S.-Y. Sun Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells Mol. Cancer Ther., November 1, 2008; 7(11): 3556 - 3565. [Abstract] [Full Text] [PDF]

				Y.-D. Lin, S. Chen, P. Yue, W. Zou, D. M. Benbrook, S. Liu, T. C. Le, K. D. Berlin, F. R. Khuri, and S.-Y. Sun CAAT/Enhancer Binding Protein Homologous Protein-Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells Cancer Res., July 1, 2008; 68(13): 5335 - 5344. [Abstract] [Full Text] [PDF]

				C. E. Whibley, K. L. McPhail, R. A. Keyzers, M. F. Maritz, V. D. Leaner, M. J. Birrer, M. T. Davies-Coleman, and D. T. Hendricks Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones Mol. Cancer Ther., September 1, 2007; 6(9): 2535 - 2543. [Abstract] [Full Text] [PDF]

				T. Liu, B. Hannafon, L. Gill, W. Kelly, and D. Benbrook Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria Mol. Cancer Ther., June 1, 2007; 6(6): 1814 - 1822. [Abstract] [Full Text] [PDF]

				M. Tiwari, A. Kumar, R. A. Sinha, A. Shrivastava, A. K. Balapure, R. Sharma, V. K. Bajpai, K. Mitra, S. Babu, and M. M. Godbole Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress Carcinogenesis, October 1, 2006; 27(10): 2047 - 2058. [Abstract] [Full Text] [PDF]

				Y. Bayon, M. A. Ortiz, F. J. Lopez-Hernandez, P. H. Howe, and F. J. Piedrafita The Retinoid Antagonist MX781 Induces Clusterin Expression in Prostate Cancer Cells via Heat Shock Factor-1 and Activator Protein-1 Transcription Factors Cancer Res., August 15, 2004; 64(16): 5905 - 5912. [Abstract] [Full Text] [PDF]