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 Dawson, M. I. Articles by Fontana, J. A. Search for Related Content PubMed PubMed Citation Articles by Dawson, M. I. Articles by Fontana, J. A.

Apoptosis Induction in Cancer Cells by a Novel Analogue of 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic Acid Lacking Retinoid Receptor Transcriptional Activation Activity¹

Department of Medicinal Chemistry, Molecular Medicine Research Institute, Mountain View, California 94043 [M. I. D., C. W. L., K-C. F., G-q. C.]; Retinoid Program, SRI, Menlo Park, California 94025 [P. D. H.]; Laboratory of Molecular Pharmacology, Oregon State University School of Pharmacy, Corvallis, Oregon 97331 [V. J. P., M. L.]; The Burnham Institute, La Jolla, California 92037 [J. G., H. L., S. K. K., X-k. Z.]; and John D. Dingell Veterans Affairs Medical Center and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201 [Y. Z., J. A. F.]

The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) is reported to have anticancer activity in vivo. Induction of cell cycle arrest and apoptosis in cancer cell lines refractory to standard retinoids suggests a retinoid-independent mechanism of action for AHPN. Conformational studies suggested that binding of AHPN does not induce an unusual conformation in retinoic acid receptor (RAR) . The 3-chloro AHPN analogue MM11453 inhibited the growth of both retinoid-resistant (HL-60R leukemia, MDA-MB-231 breast, and H292 lung) and retinoid-sensitive (MCF-7 breast, LNCaP prostate, and H460 lung) cancer cell lines by inducing apoptosis at similar concentrations. Before apoptosis, MM11453 induced transcription factor TR3 expression and loss of mitochondrial membrane potential characteristic of apoptosis. MM11453 lacked the ability to significantly activate RARs and retinoid X receptor to initiate (TREpal)₂-tk-CAT reporter transcription. These results, differential proteolysis-sensitivity assays, and glutathione S-transferase-pulldown experiments demonstrate that, unlike AHPN or the natural or standard synthetic retinoids, MM11453 does not behave as a RAR or retinoid X receptor transcriptional agonist. These studies strongly suggest that AHPN exerts its cell cycle arrest and apoptotic activity by a signaling pathway independent of retinoid receptor activation.

This article has been cited by other articles:

				S. Jogie-Brahim, D. Feldman, and Y. Oh Unraveling Insulin-Like Growth Factor Binding Protein-3 Actions in Human Disease Endocr. Rev., August 1, 2009; 30(5): 417 - 437. [Abstract] [Full Text] [PDF]

				P. M. Yamada and K.-W. Lee Perspectives in mammalian IGFBP-3 biology: local vs. systemic action Am J Physiol Cell Physiol, May 1, 2009; 296(5): C954 - C976. [Abstract] [Full Text] [PDF]

				K.-W. Lee, L. J. Cobb, V. Paharkova-Vatchkova, B. Liu, J. Milbrandt, and P. Cohen Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3 Carcinogenesis, August 1, 2007; 28(8): 1653 - 1658. [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]

				J. C. Reed and M. Pellecchia Apoptosis-based therapies for hematologic malignancies Blood, July 15, 2005; 106(2): 408 - 418. [Abstract] [Full Text] [PDF]

				K.-W. Lee, L. Ma, X. Yan, B. Liu, X.-k. Zhang, and P. Cohen Rapid Apoptosis Induction by IGFBP-3 Involves an Insulin-like Growth Factor-independent Nucleomitochondrial Translocation of RXR{alpha}/Nur77 J. Biol. Chem., April 29, 2005; 280(17): 16942 - 16948. [Abstract] [Full Text] [PDF]

				X. Cao, W. Liu, F. Lin, H. Li, S. K. Kolluri, B. Lin, Y.-h. Han, M. I. Dawson, and X.-k. Zhang Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting Mol. Cell. Biol., November 15, 2004; 24(22): 9705 - 9725. [Abstract] [Full Text] [PDF]

				S. K. Kolluri, N. Bruey-Sedano, X. Cao, B. Lin, F. Lin, Y.-H. Han, M. I. Dawson, and X.-k. Zhang Mitogenic Effect of Orphan Receptor TR3 and Its Regulation by MEKK1 in Lung Cancer Cells Mol. Cell. Biol., December 1, 2003; 23(23): 8651 - 8667. [Abstract] [Full Text] [PDF]

				I. Korichneva, J. Waka, and U. Hammerling Regulation of the Cardiac Mitochondrial Membrane Potential by Retinoids J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 426 - 433. [Abstract] [Full Text] [PDF]

				W. F. Holmes, D. R. Soprano, and K. J. Soprano Elucidation of Molecular Events Mediating Induction of Apoptosis by Synthetic Retinoids Using a CD437-resistant Ovarian Carcinoma Cell Line J. Biol. Chem., November 15, 2002; 277(47): 45408 - 45419. [Abstract] [Full Text] [PDF]

				M. A. Smith and B. Anderson Where to Next with Retinoids for Cancer Therapy? Clin. Cancer Res., October 1, 2001; 7(10): 2955 - 2957. [Full Text] [PDF]