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Pyr3, a TRPC3 channel blocker, potentiates dexamethasone sensitivity and apoptosis in acute lymphoblastic leukemia cells by disturbing Ca2+ 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 Ca2+ 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 Ca2+ signaling via only endoplasmic reticulum-released Ca2+ and exerted inhibitory effect on store-operated Ca2+ entry in dose-dependent manner in ALL cell lines. Pre-incubation of cells with Pyr3 significantly curtailed the thapsigargin- and Dex-evoked Ca2+ 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 Ca2+ 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.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02374419
Contributor : Yossan-Var Tan <>
Submitted on : Thursday, November 21, 2019 - 2:53:29 PM
Last modification on : Monday, April 27, 2020 - 3:52:16 PM

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Souleymane Abdoul-Azize, Catherine Buquet, Jean-Pierre Vannier, Isabelle Dubus. Pyr3, a TRPC3 channel blocker, potentiates dexamethasone sensitivity and apoptosis in acute lymphoblastic leukemia cells by disturbing Ca2+ signaling, mitochondrial membrane potential changes and reactive oxygen species production. European Journal of Pharmacology, Elsevier, 2016, 784, pp.90-98. ⟨10.1016/j.ejphar.2016.05.014⟩. ⟨hal-02374419⟩

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