Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice

BMC Cancer. 2010 Jun 24:10:325. doi: 10.1186/1471-2407-10-325.

Abstract

Background: The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity.

Methods: The in vivo antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model. Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days. In parallel, the molecular basis for the action of HB-19 was investigated on a melanoma cell line (called TIII) derived from a cutaneous nodule of a RET mouse.

Results: HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors, several-months delay in the incidence of large tumors, a lower frequency of cutaneous nodules, and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue. Moreover, microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls. Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition, impair anchorage-independent growth, and reduce their tumorigenic potential in mice. Moreover, HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9, and tumor necrosis factor-alpha in the TIII cells and in melanoma tumors of RET mice.

Conclusions: Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice, it delayed for several months the onset and frequency of cutaneous tumors, and exerted a significant inhibitory effect on visceral metastasis. Consequently, HB-19 could provide a novel therapeutic agent by itself or as an adjuvant therapy in association with current therapeutic interventions on a virulent cancer like melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Membrane / metabolism*
  • Cell Proliferation
  • Colony-Forming Units Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control*
  • Lung Neoplasms / secondary
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nucleolin
  • Peptide Fragments / pharmacology*
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / metabolism
  • Proto-Oncogene Proteins c-ret / physiology*
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / antagonists & inhibitors*
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Skin Neoplasms / prevention & control*
  • Survival Rate

Substances

  • Peptide Fragments
  • Phosphoproteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Proto-Oncogene Proteins c-ret