title: Hyaluronan oligomers sensitize chronic myeloid leukemia cell lines to the effect of Imatinib.
abstract: Chronic myeloid leukemia is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome (Ph), generated by a reciprocal translocation occurring between chromosomes 9 and 22 [t(9;22)(q34;q11)]. As a consequence, a fusion gene (bcr-abl) encoding a constitutively active kinase is generated. The first-line treatment consists on BCR-ABL inhibitors such as Imatinib, Nilotinib and Dasatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, finding molecules that enhance the anti-proliferative effect of first-line drugs is of value. Hyaluronan oligomers (oHA) are known to be able to sensitize several tumor cells to chemotherapy. We have previously demonstrated that oHA can revert Vincristine resistance in mouse lymphoma and human leukemia cell lines. However, little is known about the role of oHA in hematological malignancies. The aim of this work was to determine whether oHA are able to modulate the anti-proliferative effect of Imatinib in chronic myeloid leukemia (CML) cell lines. The effect on apoptosis and senescence as well as the involvement of signaling pathways were also evaluated. For this purpose, the human CML cell lines K562 and Kv562 (resistant) were used. We demonstrated that oHA sensitized both cell lines to the anti-proliferative effect of Imatinib increasing apoptosis and senescence. Moreover, this effect would be accomplished through the down-regulation of the PI3K signaling pathway. These findings highlight the potential of oHA when used as a co-adjuvant therapy for chronic myeloid leukemia.
authors.affiliation: Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires 1113, Argentina.
authors.forename: Silvina Laura
authors.initials: SL
authors.lastname: Lompardía
authors.affiliation: Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires 1113, Argentina.
authors.forename: Mariángeles
authors.initials: M
authors.lastname: Díaz
authors.affiliation: Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires 1113, Argentina.
authors.forename: Daniela Laura
authors.initials: DL
authors.lastname: Papademetrio
authors.affiliation: Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires 1113, Argentina.
authors.forename: Marilina
authors.initials: M
authors.lastname: Mascaró
authors.affiliation: Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires 1113, Argentina.
authors.forename: Matías
authors.initials: M
authors.lastname: Pibuel
authors.affiliation: Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires 1113, Argentina elialv@ffyb.uba.ar.
authors.forename: Elida
authors.initials: E
authors.lastname: Álvarez
authors.affiliation: Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires 1113, Argentina.
authors.forename: Silvia Elvira
authors.initials: SE
authors.lastname: Hajos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000068877:Imatinib Mesylate / Q000008:administration & dosage*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice
chemical_list: D000068877:Imatinib Mesylate; D006820:Hyaluronic Acid; D016044:Fusion Proteins, bcr-abl
keywords: Imatinib; apoptosis; chronic myeloid leukemia; hyaluronan oligomers; senescence