Publicaciones científicas

Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms

01-jun-2018 | Revista: Haematologica

Celay J (1), Lozano T (2), Concepcion AR (3,4), Beltrán E (1,5), Rudilla F (2), García-Barchino MJ (1), Robles EF (1), Rabal O (6), de Miguel I (6), Panizo C (7), Casares N (2), Oyarzabal J (6), Prieto J (2,3), Medina JF (3), Lasarte JJ (8), Martínez-Climent JÁ (9).

(1) Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain.
(2) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
(3) Division of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
(4) Department of Pathology, New York University School of Medicine, New York, NY, USA.
(5) Department of Pharmacology, University of Navarra, Pamplona, Spain.
(6) Small Molecule Discovery Platform and Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
(7) Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain.
(8) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
(9) Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain 


RESUMEN

Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising therapeutic approach in cancer patients.

Mice with targeted deletion of the gene encoding the Cl-/HCO3- anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells.

We therefore challenged AE2 as a potential target for tumor therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes.

Finally, a macrocyclic AE2 targeting peptide exhibiting increased stability in vivo was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies.

CITA DEL ARTÍCULO  Haematologica. 2018 Jun;103(6):1065-1072. doi: 10.3324/haematol.2017.175687. Epub 2017 Nov 30

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