EB-3D a novel choline kinase inhibitor induces deregulation of the AMPK-mTOR pathway and apoptosis in leukemia T-cells

Biochemical Pharmacology
Elena MariottoGiampietro Viola

Abstract

Choline kinase alpha 1 (ChoKα1) has recently become an interesting therapeutic target since its overexpression has been associated to tumorigenesis in many cancers. Nevertheless, little is known regarding hematological malignancies. In this manuscript, we investigated the effect of a novel and selective ChoKα inhibitor EB-3D in T acute lymphoblastic leukemia (T-ALL). The effect of EB-3D was evaluated in a panel of T-leukemia cell lines and ex-vivo primary cultures derived from pediatric T-ALL patients. We also evaluated in detail, using Reverse Phase Protein Array (RPPA), protein phosphorylation level changes in T-ALL cells upon treatment. The drug exhibits a potent antiproliferative activity in a panel of T-leukemia cell lines and primary cultures of pediatric patients. Moreover, the drug strongly induces apoptosis and more importantly it enhanced T-leukemia cell sensitivity to chemotherapeutic agents, such as dexamethasone and l-asparaginase. In addition, the compound induces an early activation of AMPK, the main regulator of cellular energy homeostasis, by its phosphorylation at residue T712 of catalytic subunit α, and thus repressing mTORC1 pathway, as shown by mTOR S2448 dephosphorylation. The inhibition of mTOR in turn af...Continue Reading

Citations

Dec 13, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Samantha GokhalePing Xie
Sep 6, 2019·Hematological Oncology·Carolina SimioniLuca M Neri
Oct 27, 2020·Medicinal Research Reviews·Belén Rubio-RuizAna Conejo-García
Feb 21, 2021·Cancer & Metabolism·Jesus Pacheco-TorresZaver M Bhujwalla
Jul 28, 2020·Advanced Drug Delivery Reviews·Lisa M ButlerJohannes V Swinnen
Jun 3, 2021·Pharmaceutics·Juan Carlos LacalJoaquín M Campos
Jul 3, 2021·Pharmaceutics·Samantha Gokhale, Ping Xie
Dec 30, 2021·Expert Review of Proteomics·Fieke W HoffSteven M Kornblau

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