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.
Dawson
M I
MI
Department of Medicinal Chemistry, Molecular Medicine Research Institute, Mountain View, California 94043, USA.
Hobbs
P D
PD
Peterson
V J
VJ
Leid
M
M
Lange
C W
CW
Feng
K C
KC
Chen Gq
Gu
J
J
Li
H
H
Kolluri
S K
SK
Zhang Xk
Zhang
Y
Y
Fontana
J A
JA
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008968:Molecular Conformation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid; D012176:Retinoids / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000187:drug effects*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C430403:MM11453; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D012176:Retinoids; D014157:Transcription Factors