PI3K/Akt inhibition modulates multidrug resistance and activates NF-kappaB in murine lymphoma cell lines.
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.
García
Mariana G
MG
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
Alaniz
Laura D
LD
Cordo Russo
Rosalía I
RI
Alvarez
Elida
E
Hajos
Silvia E
SE
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
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