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

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.

• Authors: Diala El Khoury, Damien Destouches, Renée Lengagne, Bernard Krust, Yamina Hamma-Kourbali, Marylène Garcette, Sandra Niro, Masashi Kato, Jean-Paul Briand, José Courty, Ara G Hovanessian, Armelle Prévost-Blondel
• Journal: BMC cancer (BMC Cancer) Vol. 10 Pg. 325 (Jun 24 2010) ISSN: 1471-2407 [Electronic] England
• PMID: 20573279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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