RETINOID INDUCED APOPTOSIS IN LEUKEMIA-CELLS THROUGH A RETINOIC ACID NUCLEAR RECEPTOR-INDEPENDENT PATHWAY

Trans retinoic acid (RA) has proven to be a potent therapeutic agent i n the treatment of acute promyelocytic leukemia. Unfortunately, other subtypes of acute myelogenous leukemia are resistant to the antiprolif erative and differentiating effects of RA, In this report, we describe a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene ca rboxylic acid (AHPN; CD437) that not only totally inhibits the prolife ration of RA-resistant leukemic cell lines HL-60R and K562 but also in duces apoptosis in these cells. Exposure of HL-60R to CD437 results in the rapid (within 30 minutes) increase of the cyclin-dependent kinase inhibitor p21(waf1/cip1) as well as GADD45 mRNA, Manifestations of CD 437-mediated programmed cell death are noted within 2 hours, as indica ted by both the cleavage and activation of the CPP32 protease and clea vage of poly (ADP-ribose) polymerase. This is followed by cleavage of bcl-2 and internucleosomal DNA degradation. HL-60R cells do not expres s the retinoid nuclear receptor RAR beta and RAR gamma and express a t runcated RAR alpha. Thus, CD437 induction of p21(waf1/cip1) and GADD45 mRNAs and apoptosis occurs through a unique mechanism not involving t he retinoid nuclear receptors. CD437 represents a unique retinoid with therapeutic potential in the treatment of myeloid leukemia. (C) 1997 by The American Society of Hematology.