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Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms.
- Source :
-
Haematologica [Haematologica] 2018 Jun; Vol. 103 (6), pp. 1065-1072. Date of Electronic Publication: 2017 Nov 30. - Publication Year :
- 2018
-
Abstract
- 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 <superscript>-</superscript> /HCO <subscript>3</subscript> <superscript>-</superscript> 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.<br /> (Copyright © 2018 Ferrata Storti Foundation.)
- Subjects :
- Animals
Anions metabolism
Apoptosis drug effects
Cell Line, Tumor
Cell Survival drug effects
Disease Models, Animal
Humans
Leukemia, B-Cell drug therapy
Leukemia, B-Cell pathology
Lymphoma, B-Cell drug therapy
Lymphoma, B-Cell pathology
Mice
Mice, Knockout
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Chloride-Bicarbonate Antiporters antagonists & inhibitors
Leukemia, B-Cell metabolism
Lymphoma, B-Cell metabolism
Peptides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 103
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 29191842
- Full Text :
- https://doi.org/10.3324/haematol.2017.175687