Inhibition of heat shock proteins (HSP) expression by quercetin and differential doxorubicin sensitization in neuroblastoma and Ewing's sarcoma cell lines.
Neuroblastoma (NB) and Ewing's sarcoma (ES) represent the most common extracranial solid tumors of childhood. Heat shock proteins (HSP) are elevated in cancer cells and their over-expression was correlated to drug-resistance. In this work we identified the HSP by a sensitive proteomic analysis of NB and ES cell lines, then, we studied the HSP response to doxorubicin. Some identified HSP were constitutively more expressed in NB than in ES cells. Doxorubicin-stimulated HSP response only in NB cells. Quercetin was found to inhibit HSP expression depleting heat shock factor 1 (HSF1) cellular stores. Quercetin caused a higher anti-proliferative effect in NB (IC(50): 6.9 +/- 5.8 mumol/L) than in ES cells (IC(50): 85.5 +/- 53.1 mumol/L). Moreover, quercetin caused a very pronounced doxorubicin sensitizing effect in NB cells (241 fold IC(50) decrease) and a moderate effect in ES cells. HSP involvement in NB cells sensitization was confirmed by the silencing of HSF1. Quercetin treatment and HSF1 silencing increased the pro-apoptotic effect of doxorubicin. In conclusion, the higher HSP levels, observed in NB cells, did not confer increased resistance to doxorubicin; on the contrary, HSP inhibition by quercetin or gene silencing caused higher sensitization to doxorubicin. These results may have a potential application in the treatment of NB.
Zanini
Cristina
C
Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy. cristina.zanini@unito.it
Giribaldi
Giuliana
G
Mandili
Giorgia
G
Carta
Franco
F
Crescenzio
Nicoletta
N
Bisaro
Brigitte
B
Doria
Alessandra
A
Foglia
Luiselda
L
di Montezemolo
Luca Cordero
LC
Timeus
Fabio
F
Turrini
Franco
F
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology* / Q000627:therapeutic use; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism*
D006360:Heat-Shock Proteins; D004317:Doxorubicin; D011794:Quercetin