This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Sun, S.-Y. Articles by Lotan, R. Search for Related Content PubMed PubMed Citation Articles by Sun, S.-Y. Articles by Lotan, R.

Differential Responses of Normal, Premalignant, and Malignant Human Bronchial Epithelial Cells to Receptor-selective Retinoids¹

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [S-Y. S., J. M. K., P. Y., W. K. H., R. L.]; Galderma R+D, 06905 Sophia Antipolis, France [B. S.]; Retinoid Program, SRI International, Menlo Park, California 94025 [M. I. D.]; and Retinoid Research, Allergan, Irvine, California 92623 [R. A. S. C.]

ABSTRACT

Using an in vitro lung carcinogenesis model consisting of normal, premalignant, and malignant human bronchial epithelial (HBE) cells, we analyzed the growth inhibitory effects of 26 novel synthetic retinoic acid receptor (RAR)- and retinoid X receptor (RXR)-selective retinoids. RAR-selective retinoids such as CD271, CD437, CD2325, and SR11364 showed potent activity in inhibiting the growth of either normal or premalignant and malignant HBE cells (IC₅₀s mostly <1 µM) and were much more potent than RXR-selective retinoids. Nonetheless, the combination of RAR- and RXR-selective retinoids exhibited additive effects in HBE cells. As the HBE cells became progressively more malignant, they exhibited decreased or lost sensitivity to many retinoids. The activity of the RAR-selective retinoids, with the exception of the most potent retinoid, CD437, could be suppressed by an RAR panantagonist. These results suggest that: (a) RAR/RXR heterodimers play an important role in mediating the growth inhibitory effects of most retinoids in HBE cells; (b) CD437 may act through an RAR-independent pathway; (c) some of the RAR-selective retinoids may have the potential to be used in the clinic as chemopreventive and chemotherapeutic agents for lung cancer; and (d) early stages of lung carcinogenesis may be responsive targets for chemoprevention by retinoids, as opposed to later stages.

This article has been cited by other articles:

				Z. Li, J. Zhao, Y. Du, H. R. Park, S.-Y. Sun, L. Bernal-Mizrachi, A. Aitken, F. R. Khuri, and H. Fu Down-regulation of 14-3-3{zeta} suppresses anchorage-independent growth of lung cancer cells through anoikis activation PNAS, January 8, 2008; 105(1): 162 - 167. [Abstract] [Full Text] [PDF]

				F. Lian, D. E. Smith, H. Ernst, R. M. Russell, and X.-D. Wang Apo-10'-lycopenoic acid inhibits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo Carcinogenesis, July 1, 2007; 28(7): 1567 - 1574. [Abstract] [Full Text] [PDF]

				X. Liu, P. Yue, S. Chen, L. Hu, S. Lonial, F. R. Khuri, and S.-Y. Sun The Proteasome Inhibitor PS-341 (Bortezomib) Up-Regulates DR5 Expression Leading to Induction of Apoptosis and Enhancement of TRAIL-Induced Apoptosis Despite Up-Regulation of c-FLIP and Survivin Expression in Human NSCLC Cells Cancer Res., May 15, 2007; 67(10): 4981 - 4988. [Abstract] [Full Text] [PDF]

				R. C. Winterhalder, F. R. Hirsch, G. K. Kotantoulas, W. A. Franklin, and P. A. Bunn Jr Chemoprevention of lung cancer--from biology to clinical reality Ann. Onc., February 1, 2004; 15(2): 185 - 196. [Abstract] [Full Text] [PDF]

				K. Sano, T. Takayama, K. Murakami, I. Saiki, and M. Makuuchi Overexpression of Retinoic Acid Receptor {alpha} in Hepatocellular Carcinoma Clin. Cancer Res., September 1, 2003; 9(10): 3679 - 3683. [Abstract] [Full Text] [PDF]

				N. A. Rizvi, J. L. Marshall, E. Ness, M. J. Hawkins, C. Kessler, H. Jacobs, W. D. Brenckman Jr, J. S. Lee, W. Petros, W. K. Hong, et al. Initial Clinical Trial of Oral TAC-101, a Novel Retinoic Acid Receptor-Alpha Selective Retinoid, in Patients With Advanced Cancer J. Clin. Oncol., August 15, 2002; 20(16): 3522 - 3532. [Abstract] [Full Text] [PDF]

				J. I. Song, M. N. Lango, J. D. Hwang, S. D. Drenning, Q. Zeng, W. W. Lamph, and J. R. Grandis Abrogation of Transforming Growth Factor-{alpha}/Epidermal Growth Factor Receptor Autocrine Signaling by an RXR-selective Retinoid (LGD1069, Targretin) in Head and Neck Cancer Cell Lines Cancer Res., August 1, 2001; 61(15): 5919 - 5925. [Abstract] [Full Text] [PDF]

				S.-Y. Sun, P. Yue, G. J. Kelloff, V. E. Steele, S. M. Lippman, W. K. Hong, and R. Lotan Identification of Retinamides That Are More Potent than N-(4-Hydroxyphenyl)retinamide in Inhibiting Growth and Inducing Apoptosis of Human Head and Neck and Lung Cancer Cells Cancer Epidemiol. Biomarkers Prev., June 1, 2001; 10(6): 595 - 601. [Abstract] [Full Text] [PDF]

				S. M. Lippman, J. J. Lee, D. D. Karp, E. E. Vokes, S. E. Benner, G. E. Goodman, F. R. Khuri, R. Marks, R. J. Winn, W. Fry, et al. Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer J Natl Cancer Inst, April 18, 2001; 93(8): 605 - 618. [Abstract] [Full Text] [PDF]

				I. Klaassen, R. H. Brakenhoff, S. J. Smeets, G. B. Snow, and B. J. M. Braakhuis Enhanced Turnover of all-trans-Retinoic Acid and Increased Formation of Polar Metabolites in Head and Neck Squamous Cell Carcinoma Lines Compared with Normal Oral Keratinocytes Clin. Cancer Res., April 1, 2001; 7(4): 1017 - 1025. [Abstract] [Full Text]

				S. Y. Kim, H. Adachi, J. S. Koo, and A. M. Jetten Induction of the Cytochrome P450 Gene CYP26 during Mucous Cell Differentiation of Normal Human Tracheobronchial Epithelial Cells Mol. Pharmacol., September 1, 2000; 58(3): 483 - 490. [Abstract] [Full Text]

				A. K. Virmani, A. Rathi, S. Zochbauer-Muller, N. Sacchi, Y. Fukuyama, D. Bryant, A. Maitra, S. Heda, K. M. Fong, F. Thunnissen, et al. Promoter Methylation and Silencing of the Retinoic Acid Receptor-{beta} Gene in Lung Carcinomas J Natl Cancer Inst, August 16, 2000; 92(16): 1303 - 1307. [Abstract] [Full Text] [PDF]

				S.-Y. Sun, P. Yue, L. Mao, M. I. Dawson, B. Shroot, W. W. Lamph, R. A. Heyman, R. A. S. Chandraratna, K. Shudo, W. K. Hong, et al. Identification of Receptor-selective Retinoids That Are Potent Inhibitors of the Growth of Human Head and Neck Squamous Cell Carcinoma Cells Clin. Cancer Res., April 1, 2000; 6(4): 1563 - 1573. [Abstract] [Full Text]