title: Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent.
abstract: We recently identified that the MEK/ERK1/2 pathway synergized with retinoic acid (RA) to restore both transcriptional activity and RA-induced differentiation in RA-resistant acute promyelocytic leukemia (APL) cells. To target the MEK/ERK pathway, we identified glycogen synthase kinase-3β (GSK-3β) inhibitors including lithium chloride (LiCl) as activators of this pathway in APL cells. Using NB4 (RA-sensitive) and UF-1 (RA-resistant) APL cell lines, we observed that LiCl as well as synthetic GSK-3β inhibitors decreased proliferation, induced apoptosis and restored, in RA-resistant cells, the expression of RA target genes and the RA-induced differentiation. Inhibition of the MEK/ERK1/2 pathway abolished these effects. These results were corroborated in primary APL patient cells and translated in vivo using an APL preclinical mouse model in which LiCl given alone was as efficient as RA in increasing survival of leukemic mice compared with untreated mice. When LiCl was combined with RA, we observed a significant survival advantage compared with mice treated by RA alone. In this work, we demonstrate that LiCl, a well-tolerated agent in humans, has antileukemic activity in APL and that it has the potential to restore RA-induced transcriptional activation and differentiation in RA-resistant APL cells in an MEK/ERK-dependent manner.
authors.affiliation: Service de Biologie Cellulaire AP-HP Hopital Saint-Louis, Paris, France.|Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Zassadowski
authors.affiliation: Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Pokorna
authors.affiliation: Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Ferre
authors.affiliation: Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Guidez
authors.affiliation: Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Llopis
authors.affiliation: Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Chourbagi
authors.affiliation: Departement d'Experimentation Animale, IUH, Universite Paris-Diderot, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Chopin
authors.affiliation: Laboratoire de Toxicologie Biologique, AP-HP Hopital Lariboisiere, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Poupon
authors.affiliation: Service d'Hematologie Senior, AP-HP, Hopital Saint-Louis, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Ann Padua
authors.affiliation: Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.|Departement d'Experimentation Animale, IUH, Universite Paris-Diderot, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Pla
authors.affiliation: Service de Biologie Cellulaire AP-HP Hopital Saint-Louis, Paris, France.|Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.|Universite Paris-Diderot, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: Service de Biologie Cellulaire AP-HP Hopital Saint-Louis, Paris, France.|Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Cassinat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D018021:Lithium Chloride / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D018021:Lithium Chloride