Abstract Background: We have previously shown that expression levels of the multidrug transporters ABCC1 and ABCC4, are strongly predictive of outcome in childhood neuroblastoma. Although the prognostic significance of ABCC genes is usually explained in terms of cytotoxic drug resistance, a number of observations suggested that these multidrug transporters might be contributing to the malignant phenotype independent of cytotoxic drug efflux. Methods: A MYCN-driven transgenic mouse neuroblastoma model was crossed with an Abcc1- deficient mouse strain or alternatively, treated with an ABCC1 inhibitor. ABCC genes were suppressed using siRNA or overexpressed by stable transfection in neuroblastoma cell lines. Realtime quantitative PCR was used to examine the clinical significance of ABCC family gene expression in a large prospectively accrued cohort (n=209) of primary neuroblastomas. Results: Pharmacological inhibition or genetic depletion of ABCC1 significantly inhibited neuroblastoma development in hMYCN transgenic mice (p=0.0005, p
Henderson M., Porro A., Munoz M., Iraci N., Xue C., Murray J., et al. (2011). ABCC multidrug transporters in childhood neuroblastoma: influence on tumor biology and clinical outcome, independent of cytotoxic drug efflux. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 103, 1236-1251 [10.1093/jnci/djr256].
ABCC multidrug transporters in childhood neuroblastoma: influence on tumor biology and clinical outcome, independent of cytotoxic drug efflux
PORRO, ANTONIO;IRACI, NUNZIO;GHERARDI, SAMUELE;PERINI, GIOVANNI;
2011
Abstract
Abstract Background: We have previously shown that expression levels of the multidrug transporters ABCC1 and ABCC4, are strongly predictive of outcome in childhood neuroblastoma. Although the prognostic significance of ABCC genes is usually explained in terms of cytotoxic drug resistance, a number of observations suggested that these multidrug transporters might be contributing to the malignant phenotype independent of cytotoxic drug efflux. Methods: A MYCN-driven transgenic mouse neuroblastoma model was crossed with an Abcc1- deficient mouse strain or alternatively, treated with an ABCC1 inhibitor. ABCC genes were suppressed using siRNA or overexpressed by stable transfection in neuroblastoma cell lines. Realtime quantitative PCR was used to examine the clinical significance of ABCC family gene expression in a large prospectively accrued cohort (n=209) of primary neuroblastomas. Results: Pharmacological inhibition or genetic depletion of ABCC1 significantly inhibited neuroblastoma development in hMYCN transgenic mice (p=0.0005, pI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
