title: Imatinib treatment inhibit IL-6, IL-8, NF-KB and AP-1 production and modulate intracellular calcium in CML patients.
abstract: Imatinib (IM) is considered the gold standard for chronic myeloid leukemia (CML) treatment, although resistance is emerging as a significant problem. The proinflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) play an important role in cell proliferation, survival, and resistance to glucocorticoid-mediated cell death. Several transcription factors such as NF-KB and AP-1 are activated in response to physiopathological increases and modulation of intracellular calcium levels. Our previous study demonstrated that lymphocytes from CML patients showed dysregulated calcium homeostasis and oxidative stress. Alteration in ionized calcium concentration in the cytosol has been implicated in the initiation of secretion, contraction, and cell proliferation. In this study, we hypothesized that IL-6, IL-8, NF-kB, AP-1, and intracellular calcium may be used as selective and prognostic factors to address the follow-up in CML patients treated with imatinib. Our results demonstrated a significant down-regulation in IL-6 and IL-8 release as well as NF-kB and AP-1 activation in lymphomonocytes from Imatinib-treated patients, compared to samples from untreated patients. In parallel, IM treatment, in vivo and in vitro, were able to modulate the intracellular calcium concentration of peripheral blood mononuclear cells of CML patients by acting at the level of InsP(3) receptor in the endoplasmic reticulum and at the level of the purinergic receptors on plasma membrane. The results of this study show that measurements of NF-kB, AP-1, IL-6, IL-8, and intracellular calcium in CML patients treated with Imatinib may give important information to the hematologist on diagnostic criteria and are highly predictive in patients with newly diagnosed CML.
authors.affiliation: Department of Structures, Functions and Biological Technologies, School of Veterinary Medicine, University of Naples Federico II Naples, Italy. roberto.ciarcia@unina.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciarcia
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Vitiello
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Galdiero
authors.forename: Carmen
authors.initials: C
authors.lastname: Pacilio
authors.forename: Valentina
authors.initials: V
authors.lastname: Iovane
authors.forename: Danila
authors.initials: D
authors.lastname: d'Angelo
authors.forename: David
authors.initials: D
authors.lastname: Pagnini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caparrotti
authors.forename: Daniele
authors.initials: D
authors.lastname: Conti
authors.forename: Valentina
authors.initials: V
authors.lastname: Tomei
authors.forename: Salvatore
authors.initials: S
authors.lastname: Florio
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007558:Italy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011983:Receptors, Purinergic; D018808:Transcription Factor AP-1; D000068877:Imatinib Mesylate; D002118:Calcium