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Prepublished online as a Blood First Edition Paper on September 4, 2003; DOI 10.1182/blood-2003-05-1577.
Submitted May 21, 2003
Accepted July 29, 2003
ST1926 a novel and orally active retinoid related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis
Enrico Garattini*, Edoardo Parrella, Luisa Diomede, Maurizio Gianni', Yesim Kalac, Lucio Merlini, Daniele Simoni, Romina Zanier, Fabiana F Ferrara, Ilaria Chiarucci, Paolo Carminati, Mineko Terao, and Claudio Pisano
Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Facolta di Agraria, Universita degli Studi di Milano, Milan, Italy
Facolta di Chimica, Universita di Ferrara, Milan, Italy
Department of Oncology, Sigma-Tau Industrie Farmaceutiche Riunite s.p.a., Rome, Italy
* Corresponding author; email: egarattini{at}marionegri.it.
Retinoid related molecules (RRMs) are derivatives of retinoic acid and promising anti-leukemic agents with a mechanism of action different from that of other common chemotherapeutics. Here, we describe a novel chemical series designed against the RRM prototype, CD437. This includes molecules with apoptotic effects in acute promyelocytic leukemia and other myelogenous leukemia cell lines, as well as ST2065, a RRM with antagonistic properties. The most interesting apoptotic agent is ST1926, a compound more powerful than CD437 in vitro and orally active in vivo on severe combined immunodeficiency (SCID) mice transplanted with NB4 cells. ST1926 has the same mechanism of action of CD437, as indicated by the ability to trans-activate RARg, to induce the phosphorylation of p38 and JNK, and to down-regulate the expression of many genes negatively 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, and by high concentrations of calcium blockers of the dihydropyridine type, compounds that suppress ST1926-induced apoptosis.
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