Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases

Abstract

In the NB4 model of acute promyelocytic leukemia (APL), ATRA, 9-cis retinoic acid (9-cis RA), the pan-RAR and RARaselective agonists, TTNPB and AM580, induce growth inhibition, granulocytic differentiation and apoptosis. By contrast, two RXR agonists, a RARb agonist and an anti-AP1 retinoid have very limited activity, ATRA-and AM580-dependent effects are completely inhibited by RAR antagonistic blockade, while 9-cis RA-induced cell-growth-inhibition and apoptosis are equally inhibited by RAR and RXR antagonists. ATRA, 9-cis RA and AM580 cause upregulation of the mRNAs coding for pro-caspase-1, -7, -8, and -9, which, however, results in increased synthesis of only pro-caspase-1 and -7 proteins. These phenomena are associated with activation of pro-caspase-6, -7 and -8, cytochrome c release from the mitochondria, inversion of Bcl-2/Bax ratio and degradation of PML-RARa. Caspase activation is fundamental for retinoid-induced apoptosis, which is suppressed by the caspase-inhibitor z-VAD. Cell Death and Differentiation (2000) 7, 447 ± 460.

p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells

“…Pharmacological inhibitors of p38a enhance retinoid-dependent growth inhibition and differentiation of AML cells We evaluated the consequences of p38a inhibition on ATRAinduced growth suppression and myeloid differentiation 36 of the APL-derived NB4 cell line, 31 which expresses the specific PML-RARa fusion product as well as the product of the normal RARa allele. Although inhibition of p38a by PD169316 (10 mM) exerted minor effects on the growth of NB4 cells, it enhanced the antiproliferative action of ATRA at sub-optimal concentrations (Figure 1a, left).…”

Early mitochondrial alterations in ATRA-induced cell death

“…[1][2][3][4] We and others have shown that ATRA induces maturation followed by apoptosis in a variety of different cell lines. [5][6][7][8] Differentiation induced by binding of ATRA to its nuclear retinoid receptors is detectable within 24-48 h 9 followed by apoptosis at 72-96 h. 5 It has been shown that mitochondria play an important regulatory role in ATRA-induced apoptosis. In this case, activation of proapoptotic Bcl-2 family proteins, such as Bid and Bax, results in permeabilization of the outer mitochondrial membrane and cytochrome c release.…”

All-trans-retinoic acid nanodisks

“…All-trans-retinoic acid (ATRA) is a naturally occurring vitamin A derivative that functions as a regulator of gene transcription (Umosono et al, 1988;Gianni et al, 2000;Duprez et al, 2003). ATRA interacts with members of the hormone receptor superfamily including the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) (Sun and Lotan, 2002).…”