Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression.

Affiliation

Department of Surgery, Stanford University, Stanford, CA; Department of Surgery, University of Illinois at Chicago, Chicago, IL. Electronic address: [Email]

Abstract

OBJECTIVE : MYCN oncogene amplification is an independent predictor of poor prognosis in neuroblastoma. CX-5461 is a small molecular inhibitor that prevents initiation of ribosomal RNA (rRNA) synthesis by RNA Pol I, down-regulating MYCN/MYC proteins. We hypothesize that neuroblastoma tumor growth can be suppressed by CX-5461.
METHODS : MYCN-amplified (KELLY, IMR5) and nonamplified (SY5Y, SKNAS) neuroblastoma cells were treated with CX-5461. MYCN/MYC expression after 24-48 h was determined by Western blot. Orthotopic neuroblastoma tumors created in mice using KELLY cells were treated with CX-5461-loaded silk films implanted locally. Tumor growth was monitored using ultrasound. Histologic evaluation of tumors was performed.
RESULTS : IC50 for KELLY, IMR5, SY5Y, and SKNAS cells to CX-5461 was 0.75 μM, 0.02 μM, 0.8 μM, and 1.7 μM, respectively. CX-5461 down-regulated MYCN and MYC proteins at 0.25-1.0 μM on Western blot analysis. CX-5461-loaded silk film released 23.7±3 μg of the drug in 24 h and 48.2±3.9 μg at 120 h. KELLY tumors treated with CX-5461-loaded film reached 800 mm3 after 7.8±1.4 days, while those treated with control film reached the same size on 5.1±0.6 days (p=0.03). CX-5461-treated tumors showed collapse of nucleolar hypertrophy and MYCN protein downregulation.
CONCLUSIONS : We demonstrated that local delivery of CX-5461 via sustained release platform can suppress orthotopic neuroblastoma tumor growth, especially those with MYCN/MYC overexpression.

Keywords

CX-5461,Local drug delivery platform,MYC,MYCN,Neuroblastoma,Oncogene,Silk fibroin,

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