title: Deguelin, A PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway.
abstract: Activation of the phosphoinositide 3 kinase (PI3K)/Akt signalling pathway has been linked with resistance to chemotherapeutic drugs, and its downregulation, by means of PI3K inhibitors, lowers resistance to various types of therapy in tumour cell lines. Recently, it has been reported that deguelin, a naturally occurring rotenoid, is a powerful inhibitor of PI3K. We investigated whether or not deguelin could enhance the sensitivity to chemotherapeutic drugs of human U937 leukaemia cells and acute myeloid leukaemia (AML) blasts with an activated PI3K/Akt network. Deguelin (10 nmol/l) induced S phase arrest with interference of progression to G2/M, and at 100 nmol/l significantly increased apoptotic cell death of U937. At 10-100 nmol/l concentrations, deguelin downregulated Akt phosphorylation of leukaemia cells and markedly increased sensitivity of U937 cells to etoposide or cytarabine. A 10 nmol/l concentration of deguelin did not negatively affect the survival rate of human cord blood CD34+ cells, whereas it increased sensitivity of AML blasts to cytarabine. Deguelin was less toxic than wortmannin on erythropoietin- and stem cell factor-induced erythropoiesis from CD34+ progenitor cells. Overall, our results indicate that deguelin might be used in the future for increasing sensitivity to therapeutic treatments of leukaemia cells with an active PI3K/Akt signalling network.
authors.affiliation: Dipartimento di Morfologia Umana Normale, Università di Trieste, Trieste, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortul
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Tazzari
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Billi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tabellini
authors.forename: Irina
authors.initials: I
authors.lastname: Mantovani
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cappellini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Grafone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Conte
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000208:Acute Disease; D018952:Antigens, CD34 / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003561:Cytarabine / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D005047:Etoposide / Q000627:therapeutic use; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology*; D007951:Leukemia, Myeloid / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012402:Rotenone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D003561:Cytarabine; D004921:Erythropoietin; D005047:Etoposide; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012402:Rotenone; D019089:Stem Cell Factor; C107676:deguelin