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

ABSTRACT: PURPOSE: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 ?M, 0.02 ?M, 0.8 ?M, and 1.7 ?M, respectively. CX-5461 down-regulated MYCN and MYC proteins at 0.25-1.0 ?M on Western blot analysis. CX-5461-loaded silk film released 23.7±3 ?g of the drug in 24 h and 48.2±3.9 ?g 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. CONCLUSION:We demonstrated that local delivery of CX-5461 via sustained release platform can suppress orthotopic neuroblastoma tumor growth, especially those with MYCN/MYC overexpression.

SUBMITTER: Taylor JS

PROVIDER: S-EPMC6545249 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Taylor Jordan S JS Zeki Jasmine J Ornell Kimberly K Coburn Jeannine J Shimada Hiroyuki H Ikegaki Naohiko N Chiu Bill B

Journal of pediatric surgery 20190228 6

<h4>Purpose</h4>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.<h4>Methods</h4>MYCN-amplified (KELLY, IMR5) and nonamplified (SY5Y, SKNAS) neuroblastoma cells were treated with CX-5461. MYCN/MYC expression after 24-48 h was determin ...[more]

PMID: 30879743

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Project description:Purpose:In a previous study, we demonstrated that the combination of fenretinide with lenalidomide, administered by a novel nanomicellar formulation (FLM), provided a strong antitumor effect in a neuroblastoma TrkB-expressing tumor. In this study, we tested the nanomicellar combination in an MYCN amplified neuroblastoma xenograft to assess its efficacy in different tumor genotypes and evaluate the interactions of the nanomicelles with the tumor cells. Experimental Design:FLM was administered to mice bearing human NLF xenografts to evaluate its efficacy in comparison with the nanomicelles containing fenretinide alone (FM). Confocal laser-scanning fluorescence microscopy images of the NLF cells treated with FLM and FM allowed us to estimate the nanomicelle ability to transport the encapsulated drugs inside the tumor cells. Flow cytometric analysis of the cells from treated tumors was performed to assess the effect of treatment on GD2 expression and NK cell infiltration. Results:FLM and FM decreased the growth of NLF xenografts at comparable extents during the treatment period. Afterwards, FLM induced a progressive tumor regression without regrowth, while FM treatment was followed by regrowth within 15-20 days after the end of treatment. Both FLM and FM were able to penetrate the tumor cells transporting the encapsulated drugs. FLM transported higher amount of fenretinide inside the cells. Also, FLM treatment strongly increased GD2 expression in treated tumors and slightly decreased the NK infiltration compared to FM. Conclusion:FLM treatment induced a superior antitumor response than FM in NLF xenografts, presumably due to the combined effects of fenretinide cytotoxicity and lenalidomide antiangiogenic activity. The ability of FLM to penetrate tumor cells, transporting the encapsulated drugs, substantially improved the therapeutic efficiency of this system. Moreover, the enhancement of GD2 expression in FLM treated tumors offers the possibility to further increase the antitumor effect by the use of anti-GD2 CAR-T cells and anti-GD2 antibodies in combination with FLM in multimodal therapies.

Dataset Information

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

Publications

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

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