Molecular targeting of neuroblastoma with a novel p16INK4a transporter system

Int J Oncol. 2014 Jun;44(6):1879-85. doi: 10.3892/ijo.2014.2372. Epub 2014 Apr 7.

Abstract

Potential molecular targets in neuroblastoma include ALK mutations, p16 deletion and CDK2A mutations; however, targeted therapeutics have not been developed for these factors. We developed Wr-T, a new system for intracellular peptide and protein delivery with a 30-residue sequence that mediates molecule entrapment and intracellular permeability. Wr-T was used to introduce the p16INK4a functional peptide to restore the tumor suppressor function of p16INK4a. Introduction of Wr-T into rats with subcutaneous grafts of neuroblastoma produced an astonishing 75.6% tumor suppression (p<0.0005). Thus, the p16INK4a functional peptide can be introduced in low doses and, because it exists in vivo, it should produce fewer side-effects than standard chemotherapy. We suggest this system could be used for molecular-targeted peptides other than p16INK4a and should be pursued for further development.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Cell Line, Tumor
  • Cell-Penetrating Peptides / administration & dosage
  • Cell-Penetrating Peptides / chemical synthesis
  • Cyclin-Dependent Kinase Inhibitor p16 / administration & dosage*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Drug Delivery Systems / methods
  • Female
  • HeLa Cells
  • Humans
  • Mice
  • Mice, SCID
  • Molecular Targeted Therapy / methods*
  • Neoplasms, Experimental
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Peptides / administration & dosage*
  • Peptides / chemical synthesis
  • Rats
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cell-Penetrating Peptides
  • Cyclin-Dependent Kinase Inhibitor p16
  • Peptides
  • Retinoblastoma Protein
  • Wr-T peptide