The apoptotic action of the retinoid CD437/AHPN: Diverse effects, common basis

被引:33
作者
Zhao, XS
Spanjaard, RA [1 ]
机构
[1] Boston Univ, Sch Med, Ctr Canc Res, Dept Otolaryngol, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Ctr Canc Res, Dept Biochem, Boston, MA 02118 USA
关键词
apoptosis; differentiation; CD437; AHPN; DNA adduct;
D O I
10.1159/000068087
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Retinoids, such as all-trans-retinoic acid (RA), have found applications in several different types of (cancer) therapies. The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437 or AHPN), an RA receptor (RAR)gamma agonist, not only induces RARgamma-dependent differentiation, but in contrast to RA, it also induces RARgamma-independent apoptosis in many tumor cells. This observation makes this and similar new retinoids very interesting from a clinical perspective. Several genes have been associated with CD437/AHPN-mediated apoptosis, but the multiple activities of this compound and the apparent cell-type-specific responses to treatment have made it difficult to discern a common biochemical basis for the mechanism of its apoptotic action. In this brief review, we present a model which links all CD437/AHPN-associated apoptotic effects. CD437/AHPN rapidly induces DNA adduct formation through an as-yet unknown reaction which is independent of cell type. This is followed by a cell-type-specific, largely p53-independent DNA damage response which can result in engagement of multiple cell death pathways and activation of caspases as a common endpoint. At the same time, the RARgamma-dependent pathway leads to regulation of differentiation-associated, cell-type-specific genes. CD437/AHPN, with its simultaneous differentiation and apoptosis-inducing activities, is a good prototype for new drugs which may be clinically more efficacious than those with a single activity. Copyright (C) 2003 National Science Council, ROC and S. KargerAG, Basel.
引用
收藏
页码:44 / 49
页数:6
相关论文
共 64 条
[1]   Inhibition of cell proliferation and induction of apoptosis by the retinoid AHPN in human lung carcinoma cells [J].
Adachi, H ;
Preston, G ;
Harvat, B ;
Dawson, MI ;
Jetten, AM .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1998, 18 (03) :323-333
[2]   Induction of apoptosis by the novel retinoid AHPN in human T-cell lymphoma cells involves caspase-dependent and independent pathways [J].
Adachi, H ;
Adams, A ;
Hughes, FM ;
Zhang, JD ;
Cidlowski, JA ;
Jetten, AM .
CELL DEATH AND DIFFERENTIATION, 1998, 5 (11) :973-983
[3]   The mitochondrial apoptosome: a killer unleashed by the cytochrome seas [J].
Adrain, C ;
Martin, SJ .
TRENDS IN BIOCHEMICAL SCIENCES, 2001, 26 (06) :390-397
[4]  
ASKEW DS, 1991, ONCOGENE, V6, P1915
[5]  
Benner S E, 1995, Oncology (Williston Park), V9, P205
[6]   IDENTIFICATION OF SYNTHETIC RETINOIDS WITH SELECTIVITY FOR HUMAN NUCLEAR RETINOIC ACID RECEPTOR-GAMMA [J].
BERNARD, BA ;
BERNARDON, JM ;
DELESCLUSE, C ;
MARTIN, B ;
LENOIR, MC ;
MAIGNAN, J ;
CHARPENTIER, B ;
PILGRIM, WR ;
REICHERT, U ;
SHROOT, B .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 186 (02) :977-983
[7]   Molecules in focus -: Bax.: The pro-apoptotic Bcl-2 family member, Bax [J].
Brady, HJM ;
Gil-Gómez, G .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 1998, 30 (06) :647-650
[8]   A decade of molecular biology of retinoic acid receptors [J].
Chambon, P .
FASEB JOURNAL, 1996, 10 (09) :940-954
[9]   Effects of a novel synthetic retinoid on malignant glioma in vitro:: inhibition of cell proliferation, induction of apoptosis and differentiation [J].
Costa, SL ;
Paillaud, E ;
Fages, C ;
Rochette-Egly, C ;
Plassat, JL ;
Jouault, H ;
Perzelova, A ;
Tardy, M .
EUROPEAN JOURNAL OF CANCER, 2001, 37 (04) :520-530
[10]  
Dang CV, 1999, MOL CELL BIOL, V19, P1