The apoptotic action of the retinoid CD437/AHPN: diverse effects, common basis.
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.
Zhao
Xiansi
X
Department of Otolaryngology, Cancer Research Center, Boston University School of Medicine, Boston, Mass. 02118, USA.
Spanjaard
Remco A
RA
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D018736:DNA Adducts; D004249:DNA Damage / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D012176:Retinoids / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; C099555:CD 437; D018736:DNA Adducts; D012176:Retinoids