title: Comparative effect of two pan-class I PI3K inhibitors used as anticancer drugs on human T cell function.
abstract: The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer and, thus, PI3K has been recognized as an attractive molecular target for novel anti-cancer therapies. However, the effect of PI3K inhibitors on T-cell function, a key component of antitumor immunity, has been scantly explored. The objective of this study was to investigate the effect on human T-cell activation of two PI3K inhibitors currently being tested in clinical trials: PX-866 and BKM120. Their activity against a leukemic T cell line was also assessed. For that purpose, Jurkat cells or anti-CD3/anti-CD28 stimulated human peripheral blood mononuclear cells were cultured in the presence of different concentrations of PX-866 or BKM120 and their effect on T-cell proliferation, apoptosis, expression of activation markers and cytokine secretion was analyzed by flow cytometry. In addition, Akt and Erk phosphorylation was analyzed by Western blotting. Both PX-866 and BKM120 decreased viability of Jurkat cells and blocked cell cycle progression. Regarding primary T cells, both compounds similarly inhibited expression of activation markers and cytokine secretion, although they did not induce apoptosis of stimulated T cells. Interestingly, we found differences in their ability to block T-cell proliferation and IL-2 secretion, exerting BKM120 a more potent inhibition. These disparate effects could be related to differences observed in PI3K/Akt and RAS/MEK/ERK signaling between PX-866 and BKM120 treated cells. Our results suggest that, when selecting a PI3K inhibitor for cancer therapy, immunosuppressive characteristics should be taken into account in order to minimize detrimental effects on immune function.
authors.affiliation: Department of Hematology, Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. Electronic address: bblancod@saludcastillayleon.es.
authors.forename: Belén
authors.initials: B
authors.lastname: Blanco
authors.affiliation: Department of Hematology, Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Herrero-Sánchez
authors.affiliation: Department of Hematology, Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Rodríguez-Serrano
authors.affiliation: Department of Statistics, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Sánchez-Barba
authors.affiliation: Department of Hematology, Hospital Universitario de Salamanca/Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: María Consuelo
authors.initials: MC
authors.lastname: Del Cañizo
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006067:Gonanes / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006067:Gonanes; D007376:Interleukin-2; D009025:Morpholines; C571178:NVP-BKM120; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors
keywords: Anti-tumor immunity; Cancer therapy; PI3K inhibitor; T cell