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 Sun, S.-Y. Articles by Lotan, R. Search for Related Content PubMed PubMed Citation Articles by Sun, S.-Y. Articles by Lotan, R.

The Synthetic Retinoid CD437 Selectively Induces Apoptosis in Human Lung Cancer Cells while Sparing Normal Human Lung Epithelial Cells¹

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces apoptosis in a variety of cancer cells including lung cancer cells. Our previous studies have demonstrated that cancer cells with wild-type p53 are more sensitive to CD437 than those having mutant p53, although CD437 can induce both p53-dependent and -independent apoptosis. Because normal human lung epithelial cells have wild-type p53, the question arose as to whether they are also sensitive to CD437-induced apoptosis. To address this question, we compared and contrasted the effects of CD437 on apoptosis induction and the expression of several p53-regulated apoptosis-related genes between normal human lung epithelial cells and human lung cancer cells containing wild-type p53. CD437 induced apoptosis as evidenced by apoptotic morphological changes, increased DNA fragmentation, and activation of caspase cascades in two lung cancer cell lines but not in two normal human lung epithelial cells. CD437 selectively increased the p53 protein level and concomitantly induced the expression of several p53-regulated apoptosis-related genes including Bax, Fas, DR4, and DR5 only in the two lung cancer cell lines. Furthermore, the normal lung epithelial cells, which expressed constitutively higher levels of two antiapoptotic decoy receptors DcR1 and DcR2 than lung cancer cells, exhibited an increase in the expression of these receptors after CD437 treatment, whereas no increase was detected in lung cancer cells. These results predict a differential effect of CD437 on tumor and normal cells in vivo and strongly suggest that CD437 may be a useful agent for chemoprevention and/or treatment of human cancer, especially lung cancer.

This article has been cited by other articles:

				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]

				E. Parrella, M. Gianni, M. Fratelli, M. M. Barzago, I. Raska Jr, L. Diomede, M. Kurosaki, C. Pisano, P. Carminati, L. Merlini, et al. Antitumor Activity of the Retinoid-Related Molecules (E)-3-(4'-Hydroxy-3'-adamantylbiphenyl-4-yl)acrylic Acid (ST1926) and 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437) in F9 Teratocarcinoma: Role of Retinoic Acid Receptor {gamma} and Retinoid-Independent Pathways Mol. Pharmacol., September 1, 2006; 70(3): 909 - 924. [Abstract] [Full Text] [PDF]

				F. Jin, X. Liu, Z. Zhou, P. Yue, R. Lotan, F. R. Khuri, L. W.K. Chung, and S.-Y. Sun Activation of Nuclear Factor-{kappa}B Contributes to Induction of Death Receptors and Apoptosis by the Synthetic Retinoid CD437 in DU145 Human Prostate Cancer Cells Cancer Res., July 15, 2005; 65(14): 6354 - 6363. [Abstract] [Full Text] [PDF]

				A. Arora, I. A. Siddiqui, and Y. Shukla Modulation of p53 in 7,12-dimethylbenz[a]anthracene-induced skin tumors by diallyl sulfide in Swiss albino mice Mol. Cancer Ther., November 1, 2004; 3(11): 1459 - 1466. [Abstract] [Full Text] [PDF]

				P. Mrass, M. Rendl, M. Mildner, F. Gruber, B. Lengauer, C. Ballaun, L. Eckhart, and E. Tschachler Retinoic Acid Increases the Expression of p53 and Proapoptotic Caspases and Sensitizes Keratinocytes to Apoptosis: A Possible Explanation for Tumor Preventive Action of Retinoids Cancer Res., September 15, 2004; 64(18): 6542 - 6548. [Abstract] [Full Text] [PDF]

				R. G. Keedwell, Y. Zhao, L. A. Hammond, S. Qin, K.-Y. Tsang, A. Reitmair, Y. Molina, Y. Okawa, L. I. Atangan, D.-L. Shurland, et al. A Retinoid-Related Molecule that Does Not Bind to Classical Retinoid Receptors Potently Induces Apoptosis in Human Prostate Cancer Cells through Rapid Caspase Activation Cancer Res., May 1, 2004; 64(9): 3302 - 3312. [Abstract] [Full Text] [PDF]

				E. Garattini, E. Parrella, L. Diomede, M. Gianni', Y. Kalac, L. Merlini, D. Simoni, R. Zanier, F. F. Ferrara, I. Chiarucci, et al. ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis Blood, January 1, 2004; 103(1): 194 - 207. [Abstract] [Full Text] [PDF]

				K. K. Mann, A. Rephaeli, A. L. Colosimo, Z. Diaz, A. Nudelman, I. Levovich, Y. Jing, S. Waxman, and W. H. Miller Jr. A Retinoid/Butyric Acid Prodrug Overcomes Retinoic Acid Resistance in Leukemias by Induction of Apoptosis Mol. Cancer Res., October 1, 2003; 1(12): 903 - 912. [Abstract] [Full Text] [PDF]

				Y. Honma, Y. Ishii, Y. Yamamoto-Yamaguchi, T. Sassa, and K.-i. Asahi Cotylenin A, a Differentiation-inducing Agent, and IFN-{alpha} Cooperatively Induce Apoptosis and Have an Antitumor Effect on Human Non-Small Cell Lung Carcinoma Cells in Nude Mice Cancer Res., July 1, 2003; 63(13): 3659 - 3666. [Abstract] [Full Text] [PDF]

				D. Newman, M. Sakaue, J. S. Koo, K.-S. Kim, S. J. Baek, T. Eling, and A. M. Jetten Differential Regulation of Nonsteroidal Anti-Inflammatory Drug-Activated Gene in Normal Human Tracheobronchial Epithelial and Lung Carcinoma Cells by Retinoids Mol. Pharmacol., March 1, 2003; 63(3): 557 - 564. [Abstract] [Full Text] [PDF]