title: Pyr3, a TRPC3 channel blocker, potentiates dexamethasone sensitivity and apoptosis in acute lymphoblastic leukemia cells by disturbing Ca(2+) signaling, mitochondrial membrane potential changes and reactive oxygen species production.
abstract: Dexamethasone (Dex) is used as a chemotherapeutic drug in the treatment of acute lymphoblastic leukemia (ALL) because of its capacity to induce apoptosis. However, some ALL patients acquire resistance to glucocorticoids (GC). Thus, it is important to explore new agents to overcome GC resistance. The aim of the present work was to assess the ability of Pyr3, a selective inhibitor of transient receptor potential canonical 3 (TRPC3), to sensitize human ALL cells to Dex. We show here, for the first time, that Pyr3 enhances Dex sensitivity through the distraction of Dex-mediated Ca(2+) signaling in ALL cells (in vitro) and primary blasts (ex vivo) associated with mitochondrial-mediated reactive oxygen species production in ALL cells. Pyr3 alone induced Ca(2+) signaling via only endoplasmic reticulum-released Ca(2+) and exerted inhibitory effect on store-operated Ca(2+) entry in dose-dependent manner in ALL cell lines. Pre-incubation of cells with Pyr3 significantly curtailed the thapsigargin- and Dex-evoked Ca(2+) signaling in ALL cell lines. Pyr3 synergistically potentiated Dex lethality, as shown by the induction of cell mortality, G2/M cell cycle arrest and apoptosis in ALL cell lines. Moreover, Pyr3 disrupted Dex-mediated Ca(2+) signaling and increased the sensitivity of Dex-induced cell death in primary blasts from ALL patients. Additional analysis showed that co-treatment with Dex and Pyr3 results in mitochondrial membrane potential depolarization and reactive oxygen species production in ALL cells. Together, Pyr3 exhibited potential therapeutic benefit in combination with Dex to inverse glucocorticoid resistance in human ALL and probably in other lymphoid malignancies.
authors.affiliation: Groupe de Recherche "Micro-Environnement et Renouvellement Cellulaire Intégré" MERCI UPRES EA 3829, Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France. Electronic address: souleymane.abdoul-azize@univ-rouen.fr.
authors.forename: Souleymane
authors.initials: S
authors.lastname: Abdoul-Azize
authors.affiliation: Groupe de Recherche "Micro-Environnement et Renouvellement Cellulaire Intégré" MERCI UPRES EA 3829, Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Buquet
authors.affiliation: Groupe de Recherche "Micro-Environnement et Renouvellement Cellulaire Intégré" MERCI UPRES EA 3829, Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France; Service Immuno-Hémato-Oncologie Pédiatrique, CHU Charles Nicolle, 76031 Rouen Cedex, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vannier
authors.affiliation: Groupe de Recherche "Micro-Environnement et Renouvellement Cellulaire Intégré" MERCI UPRES EA 3829, Faculté de Médecine et Pharmacie, Université de Rouen, 76183 Rouen Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dubus
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors
chemical_list: D011720:Pyrazoles; D017382:Reactive Oxygen Species; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C559943:ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate; D003907:Dexamethasone
keywords: Acute lymphoblastic leukemia; Apoptosis, Reactive oxygen species; Calcium signaling; Dexamethasone; Pyr3