Retinoid-related mols. (RRMs) are derivs. of retinoic acid and promising antileukemic agents with a mechanism of action different from that of other common chemotherapeutics. Here, we describe a novel chem. series designed against the RRM prototype, CD437. This includes mols. with apoptotic effects in acute promyelocytic leukemia and other myelogenous leukemia cell lines, as well as ST2065, an RRM with antagonistic properties. The most interesting apoptotic agent is ST1926, a compd. more powerful than CD437 in vitro and orally active in vivo on severe combined immunodeficiency (SCID) mice that received transplants of NB4 cells. ST1926 has the same mechanism of action of CD437, as indicated by the ability to trans-activate retinoic acid receptor g, to induce the phosphorylation of p38 and JNK, and to down-regulate the expression of many genes neg. modulated by CD437. ST1926 causes an immediate increase in the cytosolic levels of calcium that are directly related to the apoptotic potential of the RRMs considered. The intracellular calcium elevation is predominantly the result of an inhibition of the mitochondrial calcium uptake. The phenomenon is blocked by the ST2065 antagonist, the intracellular calcium chelator BAPTA 1,2 bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid tetrakis (acetoxymethyl ester), and by high concns. of calcium blockers of the dihydropyridine type, compds. that suppress ST1926-induced apoptosis.
|Titolo:||ST1926: a novel and orally active retinoid related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis|
|Parole Chiave:||ST 1926, apoptosis, myeloid leukemia, calcium homeostasis, retinoids|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Data di pubblicazione:||2004|
|Digital Object Identifier (DOI):||10.1182/blood-2003-05-1577|
|Appare nelle tipologie:||01 - Articolo su periodico|