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

PLoS One. 2014 Mar 6;9(3):e90224. doi: 10.1371/journal.pone.0090224. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cimetidine / administration & dosage
  • Cyclophosphamide / administration & dosage
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Diclofenac / administration & dosage
  • Drug Administration Schedule
  • Drug Combinations
  • Drug Synergism
  • Gemcitabine
  • Gene Amplification*
  • Humans
  • Immunohistochemistry
  • Magnetic Resonance Imaging / methods*
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • N-Myc Proto-Oncogene Protein
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neuroblastoma / blood supply
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Nuclear Proteins / genetics*
  • Oncogene Proteins / genetics*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Sulfasalazine / administration & dosage
  • Treatment Outcome
  • Tretinoin / administration & dosage
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays*


  • Drug Combinations
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • TL-118
  • Deoxycytidine
  • Diclofenac
  • Sulfasalazine
  • Tretinoin
  • Cimetidine
  • Cyclophosphamide
  • Gemcitabine

Grants and funding

This research was supported by a grant from the Israeli Cancer Association (20130099) and a financial support from Manferd and Sabine Landau (London). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.