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

The synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carbox ylic acid (CD437), which was originally developed as an retinoic acid recep tor (RAR)-gamma agonist, induces rapid apoptosis in all-trans retinoic acid (ATRA)sensitive and ATRA-resistant clones of the NB4 cell line, a widely u sed experimental model of acute promyelocytic leukemia (APL). In addition, the compound is apoptogenic in primary cultures of freshly isolated APL bla sts obtained from a newly diagnosed case and an ATRA-resistant relapsed pat ient. NB4 cells in the S-phase of the cycle are most sensitive to CD437-tri ggered apoptosis. CD437-dependent apoptosis does not require de novo protei n synthesis and activation of RAR-gamma or any of the other nuclear retinoi c acid receptors. The process is preceded by rapid activation of a caspase- like enzymatic activity capable of cleaving the fluorogenic DEVD but not th e fluorogenic YVAD tetrapeptide. Increased caspase activity correlates with caspase-3 and caspase-7 activation. Inhibition of caspases by z-VAD suppre sses the nuclear DNA degradation observed in NB4 cells treated with CD437. as well as the degradation of procaspase-3 and pro-caspase-7. CD437-depende nt activation of caspases is preceded by release Of cytochrome c from the m itochondria 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 leukemi a-RAR-alpha, which can be completely inhibited by z-VAD. (C) 1999 by The Am erican Society of Hematology.