Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity.

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) gamma. 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 alpha 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 alpha 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.

[1]  R. Lotan,et al.  Implication of multiple mechanisms in apoptosis induced by the synthetic retinoid CD437 in human prostate carcinoma cells , 2000, Oncogene.

[2]  D. Moras,et al.  Structural basis for isotype selectivity of the human retinoic acid nuclear receptor. , 2000, Journal of molecular biology.

[3]  John Calvin Reed,et al.  Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. , 2000, Science.

[4]  D. Moras,et al.  Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. Nagpal,et al.  Recent developments in receptor-selective retinoids. , 2000, Current pharmaceutical design.

[6]  M. Widschwendter,et al.  Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. , 2000, Journal of the National Cancer Institute.

[7]  A. Rishi,et al.  Identification of a unique binding protein specific for a novel retinoid inducing cellular apoptosis , 2000, International journal of cancer.

[8]  Y Li,et al.  [Mitochondria and apoptosis]. , 2000, Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine].

[9]  D. Xiao,et al.  Orphan Receptor COUP-TF Is Required for Induction of Retinoic Acid Receptor β, Growth Inhibition, and Apoptosis by Retinoic Acid in Cancer Cells , 2000, Molecular and Cellular Biology.

[10]  K. Fukasawa,et al.  p53 Mutation and Mitotic Infidelity , 2000, Cancer investigation.

[11]  M. Dawson,et al.  Synthetic retinoids and their usefulness in biology and medicine , 2000 .

[12]  B. Joseph,et al.  The novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid can trigger apoptosis through a mitochondrial pathway independent of the nucleus. , 1999, Cancer research.

[13]  S. Hsu,et al.  Involvement of cyclin-dependent kinase activities in CD437-induced apoptosis. , 1999, Experimental cell research.

[14]  M. Sheikh,et al.  Post-transcriptional regulation of the DNA damage-inducible gadd45 gene in human breast carcinoma cells exposed to a novel retinoid CD437. , 1999, Nucleic acids research.

[15]  M. Leid,et al.  Identification of Nuclear Receptor Corepressor as a Peroxisome Proliferator-activated Receptor α Interacting Protein* , 1999, The Journal of Biological Chemistry.

[16]  M. Dawson,et al.  Synthetic retinoid CD437 induces S‐phase arrest and apoptosis in human prostate cancer cells LNCaP and PC‐3 , 1999, The Prostate.

[17]  N. Picard,et al.  A selective retinoid with high activity against an androgen‐resistant prostate cancer cell type , 1999, International journal of cancer.

[18]  J. Cidlowski,et al.  Induction of apoptosis by the novel retinoid AHPN in human T-cell lymphoma cells involves caspase-dependent and independent pathways , 1998, Cell Death and Differentiation.

[19]  John Calvin Reed,et al.  Molecular Determinants of AHPN (CD437)-Induced Growth Arrest and Apoptosis in Human Lung Cancer Cell Lines , 1998, Molecular and Cellular Biology.

[20]  M. Widschwendter,et al.  Antiproliferative activity and apoptosis induced by retinoic acid receptor-gamma selectively binding retinoids in neuroblastoma. , 1998, Anticancer research.

[21]  M. Leid,et al.  p300 Functions as a Coactivator for the Peroxisome Proliferator-activated Receptor α* , 1997, The Journal of Biological Chemistry.

[22]  A. Muñoz,et al.  Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway. , 1997, Genes & development.

[23]  M. V. Heiden,et al.  Bcl-xL Regulates the Membrane Potential and Volume Homeostasis of Mitochondria , 1997, Cell.

[24]  Y. Li,et al.  Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids , 1997, Molecular and cellular biology.

[25]  R. Chandraratna,et al.  Lack of involvement of retinoic acid receptor alpha in retinoid-induced skin irritation in hairless mice. , 1997, Toxicology letters.

[26]  A. Rishi,et al.  Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway. , 1997, Blood.

[27]  N. Picard,et al.  Novel retinoid-related molecules as apoptosis inducers and effectve inhibitors of human lung cancer cells in vivo , 1997, Nature Medicine.

[28]  M. Widschwendter,et al.  Activity of retinoic acid receptor‐γ selectively binding retinoids alone and in combination with interferon‐γ in breast cancer cell lines , 1997 .

[29]  Q. Wu,et al.  Effects of receptor class- and subtype-selective retinoids and an apoptosis-inducing retinoid on the adherent growth of the NIH:OVCAR-3 ovarian cancer cell line in culture. , 1997, Cancer letters.

[30]  R. Lotan,et al.  Rapid induction of apoptosis in human C33A cervical carcinoma cells by the synthetic retinoid 6‐[3‐(1‐adamantyl)hydroxyphenyl]‐2‐naphtalene carboxylic acid (CD437) , 1997, International journal of cancer.

[31]  I B Dawid,et al.  Retinoid X receptor (RXR) within the RXR-retinoic acid receptor heterodimer binds its ligand and enhances retinoid-dependent gene expression , 1997, Molecular and cellular biology.

[32]  X. -. Li,et al.  Posttranscriptional regulation of p21WAF1/CIP1 expression in human breast carcinoma cells. , 1996, Cancer research.

[33]  John Calvin Reed,et al.  Retinoic acid receptor beta mediates the growth-inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells , 1996, Molecular and cellular biology.

[34]  B. Shroot,et al.  Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. , 1995, Journal of medicinal chemistry.

[35]  John Calvin Reed,et al.  Overexpression of the Bcl-2 Protein Increases the Half-life of p21Bax(*) , 1995, The Journal of Biological Chemistry.

[36]  Thorsten Heinzel,et al.  Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor , 1995, Nature.

[37]  Z. Shao,et al.  N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. , 1995, Carcinogenesis.

[38]  K. R. Ely,et al.  Correlation of retinoid binding affinity to retinoic acid receptor alpha with retinoid inhibition of growth of estrogen receptor-positive MCF-7 mammary carcinoma cells. , 1995, Cancer research.

[39]  M. Sheikh,et al.  p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. , 1995, Oncogene.

[40]  J. Starrett,et al.  Role of retinoic acid receptor gamma in the Rhino mouse and rabbit irritation models of retinoid activity. , 1995, Skin pharmacology : the official journal of the Skin Pharmacology Society.

[41]  D. Schadendorf,et al.  Retinoic Acid receptor-gamma-selective retinoids exert antiproliferative effects on human-melanoma cell-growth in-vitro. , 1994, International journal of oncology.

[42]  M. Leid.  Ligand-induced alteration of the protease sensitivity of retinoid X receptor alpha. , 1994, The Journal of biological chemistry.

[43]  Pemrick Sm,et al.  The retinoid receptors. , 1994 .

[44]  S. Pemrick,et al.  The retinoid receptors. , 1994, Leukemia.

[45]  S. Ménard,et al.  N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid. , 1993, Cancer research.

[46]  A. Fanjul,et al.  Retinoic acid receptors and retinoid X receptor-alpha down-regulate the transforming growth factor-beta 1 promoter by antagonizing AP-1 activity. , 1993, Molecular endocrinology.

[47]  H. Koeffler,et al.  9-cis-retinoic acid: effects on normal and leukemic hematopoiesis in vitro. , 1993, Blood.

[48]  K. Robertson,et al.  Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity. , 1992, Blood.

[49]  B. Shroot,et al.  Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. , 1992, Biochemical and biophysical research communications.

[50]  M. Pfahl,et al.  Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors , 1992, Nature.

[51]  Philippe Kastner,et al.  Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently , 1992, Cell.

[52]  J. Y. Chen,et al.  Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. , 1992, Cell.

[53]  M. Pfahl,et al.  6'-substituted naphthalene-2-carboxylic acid analogs, a new class of retinoic acid receptor subtype-specific ligands. , 1991, Biochemical and biophysical research communications.