title: PI3K/Akt inhibition modulates multidrug resistance and activates NF-kappaB in murine lymphoma cell lines.
abstract: Upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been described in some tumors related to multidrug resistance (MDR). The aim of this work was to analyze the relationship between PI3K/Akt, MDR and NF-kappaB in murine lymphoma cell lines resistant to vincristine (LBR-V160) and doxorubicin (LBR-D160) as well as in the sensitive line (LBR-). PI3K/Akt activity, analyzed by phosphatidylinositol trisphosphate production and phosphorylated Akt (p-Akt) expression, was higher in the resistant cell lines than in the sensitive one and inhibition with wortmannin or LY294002 improved apoptosis in the resistant cell lines. Vincristine but not doxorubicin increased p-Akt expression whereas co-treatment with PI3K inhibitors and vincristine increased apoptosis in the three cell lines. Wortmannin and LY294002 inhibited P-glycoprotein (Pgp) function and also increased NF-kappaB activity. We concluded that the PI3K/Akt pathway is involved in MDR in lymphoma cell lines and PI3K/Akt inhibition correlates down-regulation of NF-kappaB activity and inhibition Pgp function.
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, IDEHU-CONICET, Junin 956 4 piso, 1113 Ciudad de Buenos Aires, Argentina. marianag@ffyb.uba.ar
authors.forename: Mariana G
authors.initials: MG
authors.lastname: García
authors.forename: Laura D
authors.initials: LD
authors.lastname: Alaniz
authors.forename: Rosalía I
authors.initials: RI
authors.lastname: Cordo Russo
authors.forename: Elida
authors.initials: E
authors.lastname: Alvarez
authors.forename: Silvia E
authors.initials: SE
authors.lastname: Hajos
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014750:Vincristine; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt