The novel synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2- naphthalene carboxylic acid (CD437) causes apoptosis in acute promyelocytic leukemia cells through rapid activation of caspases

Luca Mologni, Isabella Ponzanelli, Filippo Bresciani, Gabriele Sardiello, Daniele Bergamaschi, Maurizio Gianní, Uwe Reichert, Alessandro Rambaldi, Mineko Terao, Enrico Garattini

Research output: Contribution to journalArticle

Abstract

The synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which was originally developed as an retinoic acid receptor (RAR)-γ agonist, induces rapid apoptosis in all-trans retinoic acid (ATRA)-sensitive and ATRA-resistant clones of the NB4 cell line, a widely used experimental model of acute promyelocytic leukemia (APL). In addition, the compound is apoptogenic in primary cultures of freshly isolated APL blasts obtained from a newly diagnosed case and an ATRA-resistant relapsed patient. NB4 cells in the S-phase of the cycle are most sensitive to CD437- triggered apoptosis. CD437-dependent apoptosis does not require de novo protein synthesis and activation of RAR-γ or any of the other nuclear retinoic acid receptors. The process is preceded by rapid activation of a caspase-like enzymatic activity capable of cleaving the fluorogenic DEVD but not the fluorogenic YVAD tetrapeptide. Increased caspase activity correlates with caspase-3 and caspase-7 activation. Inhibition of caspases by z-VAD suppresses the nuclear DNA degradation observed in NB4 cells treated with CD437, as well as the degradation of pro-caspase-3 and pro-caspase-7. CD437- dependent activation of caspases is preceded by release of cytochrome c from the mitochondria into the cytosol of treated cells. Leakage of cytochrome c lays upstream of caspase activation, because the phenomenon is left unaffected by pretreatment of NB4 cells with z-VAD. Treatment of APL cells with CD437 is associated with a caspase-dependent degradation of promyelocytic leukemia-RAR-α, which can be completely inhibited by z-VAD.

Original languageEnglish
Pages (from-to)1045-1061
Number of pages17
JournalBlood
Volume93
Issue number3
Publication statusPublished - Feb 1 1999

ASJC Scopus subject areas

  • Hematology

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