RESUMO
Anthracyclines have been a cornerstone in the cure of diffuse large B-cell lymphoma (DLBCL) and other hematological cancers. The ability of anthracyclines to eliminate DLBCL depends on the presence of topoisomerase-II-alpha (TopIIA), a DNA repair enzyme complex. We identified nucleolin as a novel binding partner of TopIIA. Abrogation of nucleolin sensitized DLBCL cells to TopIIA targeting agents (doxorubicin/etoposide). Silencing nucleolin and challenging DLBCL cells with doxorubicin enhanced the phosphorylation of H2AX (γH2AX-marker of DNA damage) and allowed DNA fragmentation. Reconstitution of nucleolin expression in nucleolin-knockdown DLBCL cells prevented TopIIA targeting agent-induced apoptosis. Nucleolin binding to TopIIA was mapped to RNA-binding domain 3 of nucleolin, and this interaction was essential for blocking DNA damage and apoptosis. Nucleolin silencing decreased TopIIA decatenation activity, but enhanced formation of TopIIA-DNA cleavable complexes in the presence of etoposide. Moreover, combining nucleolin inhibitors: aptamer AS1411 or nucant N6L with doxorubicin reduced DLBCL cell survival. These findings are of clinical importance because low nucleolin levels versus high nucleolin levels in DLBCL predicted 90-month estimated survival of 70% versus 12% (P<0.0001) of patients treated with R-CHOP-based therapy.
Assuntos
Antineoplásicos/farmacologia , Linfoma Difuso de Grandes Células B/metabolismo , Fosfoproteínas/antagonistas & inibidores , Proteínas de Ligação a RNA/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , DNA Topoisomerases Tipo II/metabolismo , Feminino , Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Terapia de Alvo Molecular , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , NucleolinaRESUMO
A study was carried out on 180 sera collected from inhabitants of a seepage flooded village (Begiram) in a Nile Delta governorate in Egypt. The aim of the study was to monitor the prevalence of certain arboviruses; some of them are known to be endemic in Egypt. Sera were screened by ELISA except for the HTN by IF, and the results indicated that WN and SFS exhibited the highest prevalence 45.5% followed by SFN (21%). These 3 viruses are known to be endemic in Egypt. The high prevalence of W.N. and S.F.S viruses in Begiram village in comparison to lower rates detected in sera from nearby Sharkqiya governorate collected almost at the same time may reflect the adverse effect of the environmental change in the flooded village. RNF virus which caused a major epidemic in Egypt in 1977 and continued to be circulating until 1980, its antibodies were detected only in those above 20 years of age with a prevalence rate of 5%. Antibodies against two tick borne viruses viz QRF and CCHF were also detected with low prevalence rate 2.75% and 1.1% respectively; also antibodies to the rodent-borne HTN virus were detected with prevalence rate 1.1%. Antibodies to mosquito borne SIN and BAT viruses were not detected in the tested sera.
