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Identification of Receptor-selective Retinoids That Are Potent Inhibitors of the Growth of Human Head and Neck Squamous Cell Carcinoma Cells¹

Department of Thoracic/Head and Neck Medical Oncology [S-Y. S., P. Y., L. M., W. K. H., R. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Retinoid Program, SRI International, Menlo Park, California 94025 [M. I. D.]; Galderma Research and Development, 06905 Sophia Antipolis, France [B. S.]; Cell Biology, Ligand Pharmaceuticals Inc., San Diego, California 92121 [W. W. L., R. A. H.]; Retinoid Research, Allergan, Irvine, California 92623 [R. A. S. C.]; and Faculty of Pharmaceutical Sciences, Tokyo University, Tokyo 113, Japan [K. S.]

Retinoids modulate the growth and differentiation of cancer cells presumably by activating gene transcription via the nuclear retinoic acid receptor (RAR) , ß, and and retinoid X receptor (RXR) , ß, and . We analyzed the effects of 38 RAR-selective and RXR-selective retinoids on the proliferation of 10 human head and neck squamous cell carcinoma (HNSCC) cell lines. All of these cell lines expressed constitutively all of the receptor subtypes except RARß, which was detected in only two of them. Most of the RAR-selective retinoids inhibited the growth of HNSCC cells to varying degrees, whereas the RXR-selective retinoids showed very weak or no inhibitory effects. Three RAR antagonists suppressed growth inhibition by RAR-selective agonists, as well as by RAR/RXR panagonists such as 9-cis-retinoic acid. Combinations of RXR-selective and RAR-selective retinoids exhibited additive growth-inhibitory effects. Furthermore, we found that CD437, the most potent growth-inhibitory retinoid induced apoptosis and up-regulated the expression of several apoptosis-related genes in HNSCC cells. These results indicate that: (a) retinoid receptors are involved in the growth-inhibitory effects of retinoids; (b) RXR-RAR heterodimers rather than RXR-RXR homodimer are the major mediators of growth inhibition by retinoids in HNSCC cells; and (c) induction of apoptosis can account for one mechanism by which retinoids such as CD437 inhibit the growth of HNSCC cells. Finally, these studies identified several synthetic retinoids, which are much more effective than the natural RAs and can be good candidates for chemoprevention and therapy of head and neck cancers.

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