title: Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia.
abstract: An attractive molecular target for novel anti-cancer therapies is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway which is commonly deregulated in many types of cancer. Nevertheless, the effects of PI3K/Akt/mTOR inhibitors on T lymphocytes, a key component of immune responses, have been seldom explored. In this study we investigated the effects on human CD4+ T-cells of a panel of PI3K/Akt/mTOR inhibitors: BGT226, Torin-2, MK-2206, and ZSTK474. We also assessed their efficacy against two acute leukemia T cell lines. T lymphocytes were stimulated with phytohemagglutinin. Inhibitor effects on cell cycle and apoptosis were analyzed by flow cytometry, while cytotoxicity was assessed by MTT assays. In addition, the activation status of the pathway as well as induction of autophagy were analyzed by Western blotting. Quiescent healthy T lymphocytes were unaffected by the drugs whereas mitogen-stimulated lymphocytes as well as leukemic cell lines displayed a cell cycle block, caspase-dependent apoptosis, and dephosphorylation of key components of the signaling pathway. Autophagy was also induced in proliferating lymphocytes and in JURKAT and MOLT-4 cell lines. When autophagy was inhibited by 3-methyladenine or Bafilomycin A1, drug cytotoxicity was increased, indicating that autophagy is a protective mechanism. Therefore, our findings suggest that PI3K/Akt/mTOR inhibitors preserve lymphocyte viability. This is a valuable result to be taken into account when selecting drugs for targeted cancer therapy in order to minimize detrimental effects on immune function.
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|Department of Chemical Pathology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan.
authors: Ayman A M
authors: AA
authors: Alameen
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Carolina
authors: C
authors: Simioni
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Alberto M
authors: AM
authors: Martelli
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Giorgio
authors: G
authors: Zauli
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Simona
authors: S
authors: Ultimo
authors: Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors: James A
authors: JA
authors: McCubrey
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Arianna
authors: A
authors: Gonelli
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Giorgia
authors: G
authors: Marisi
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Paola
authors: P
authors: Ulivi
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|LTTA Center, University of Ferrara, Ferrara, Italy.
authors: Silvano
authors: S
authors: Capitani
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Luca M
authors: LM
authors: Neri
mesh_terms: D001343:Autophagy / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008213:Lymphocyte Activation; D058990:Molecular Targeted Therapy; D009287:Naphthyridines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; D007093:Imidazoles; D009287:Naphthyridines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: PI3K/Akt/mTOR signaling; T lymphocytes; T-acute lymphoblastic leukemia; autophagy; targeted therapies