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TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.

ABSTRACT: Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor with up to 50% of NB patients classified as having high-risk disease with poor long-term survival rates. The poor clinical outcome and aggressiveness of high-risk NB strongly correlates with enhanced angiogenesis, suggesting anti-angiogenic agents as attractive additions to the currently insufficient therapeutics. TL-118, a novel drug combination has been recently developed to inhibit tumor angiogenesis. In the current study, we used the SK-N-BE (2) cell line to generate orthotopic NB tumors in order to study the combinational therapeutic potential of TL-118 with either Gemcitabine (40 mg/kg; IP) or Retinoic acid (40 mg/kg; IP). We show that TL-118 treatment (n?=?9) significantly inhibited tumor growth, increased cell apoptosis, reduced proliferation and extended mouse survival. Moreover, the reciprocal effect of TL-118 and Gemcitabine treatment (n?=?10) demonstrated improved anti-tumor activity. The synergistic effect of these drugs in combination was more effective than either TL or Gemcitabine alone (n?=?9), via significantly reduced cell proliferation (p<0.005), increased apoptosis (p<0.05) and significantly prolonged survival (2-fold; p<0.00001). To conclude, we demonstrate that the novel drug combination TL-118 has the ability to suppress the growth of an aggressive NB tumor. The promising results with TL-118 in this aggressive animal model may imply that this drug combination has therapeutic potential in the clinical setting.

SUBMITTER: Komar-Stossel C

PROVIDER: S-EPMC3946152 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.

Komar-Stossel Chani C Gross Eitan E Dery Elia E Corchia Nathalie N Meir Karen K Fried Iris I Abramovitch Rinat R

PloS one 20140306 3

Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor with up to 50% of NB patients classified as having high-risk disease with poor long-term survival rates. The poor clinical outcome and aggressiveness of high-risk NB strongly correlates with enhanced angiogenesis, suggesting anti-angiogenic agents as attractive additions to the currently insufficient therapeutics. TL-118, a novel drug combination has been recently developed to inhibit tumor angiogenesis. In the current stu ...[more]

PMID: 24603724

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Project description:Neuroblastoma derived from primitive sympathetic neural precursors is a common type of solid tumor in infants. MYCN proto?oncogene bHLH transcription factor (MYCN) amplification and 1p36 deletion are important factors associated with the poor prognosis of neuroblastoma. Expression levels of MYCN and c?MYB proto?oncogene transcription factor (c?myb) decline during the differentiation of neuroblastoma cells; E2F transcription factor 1 (E2F1) activates the MYCN promoter. However, the underlying mechanism of MYCN overexpression and amplification requires further investigation. In the present study, potential c?Myb target genes, and the effect of c?myb RNA interference (RNAi) on MYCN expression and amplification were investigated in MYCN?amplified neuroblastoma cell lines. The mRNA expression levels and MYCN gene copy number in five neuroblastoma cell lines were determined by quantitative polymerase chain reaction. In addition, variations in potential target gene expression and MYCN gene copy number between pre? and post?c?myb RNAi treatment groups in MYCN?amplified Kelly, IMR32, SIMA and MHH?NB?11 cell lines, normalized to those of non?MYCN?amplified SH?SY5Y, were examined. To determine the associations between gene expression levels and chromosomal aberrations, MYCN amplification and 1p36 alterations in interphases/metaphases were analyzed using fluorescence in situ hybridization. Statistical analyses revealed correlations between 1p36 alterations and the expression of c?myb, MYB proto?oncogene like 2 (B?myb) and cyclin dependent kinase inhibitor 1A (p21). Additionally, the results of the present study also demonstrated that c?myb may be associated with E2F1 and L3MBTL1 histone methyl?lysine binding protein (L3MBTL1) expression, and that E2F1 may contribute to MYCN, B?myb, p21 and chromatin licensing and DNA replication factor 1 (hCdt1) expression, but to the repression of geminin (GMNN). On c?myb RNAi treatment, L3MBTL1 expression was silenced, while GMNN was upregulated, indicating G2/M arrest. In addition, MYCN gene copy number increased following treatment with c?myb RNAi. Notably, the present study also reported a 43.545% sequence identity between upstream of MYCN and Drosophila melanogaster amplification control element 3, suggesting that expression and/or amplification mechanisms of developmentally?regulated genes may be evolutionarily conserved. In conclusion, c?myb may be associated with regulating MYCN expression and amplification. c?myb, B?myb and p21 may also serve a role against chromosome 1p aberrations. Together, it was concluded that MYCN gene is amplified during S phase, potentially via a replication?based mechanism.

Dataset Information

TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.

Publications

TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.

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