ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis.
Retinoid-related molecules (RRMs) are derivatives of retinoic acid and promising antileukemic 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, an 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 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 gamma, 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 (1,2 bis (2-aminophenoxy) ethane-N, N, N',N'-tetraacetic acid tetrakis (acetoxymethyl ester), and by high concentrations of calcium blockers of the dihydropyridine type, compounds that suppress ST1926-induced apoptosis.
Garattini
Enrico
E
Laboratory of Molecular Biology, Centro Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy. egarattini@marionegri.it
Parrella
Edoardo
E
Diomede
Luisa
L
Gianni'
Maurizio
M
Kalac
Yesim
Y
Merlini
Lucio
L
Simoni
Daniele
D
Zanier
Romina
R
Ferrara
Fabiana Fosca
FF
Chiarucci
Ilaria
I
Carminati
Paolo
P
Terao
Mineko
M
Pisano
Claudio
C
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D000097768:Retinoic Acid Receptor gamma
D000218:Adamantane; D000970:Antineoplastic Agents; D002118:Calcium; D002614:Chelating Agents; D002934:Cinnamates; D004095:Dihydropyridines; D004533:Egtazic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D048051:p38 Mitogen-Activated Protein Kinases; D000097768:Retinoic Acid Receptor gamma; C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; C099555:CD 437; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid