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.
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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)
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Chemical References |
- Peptide Fragments
- Phosphoproteins
- RNA, Messenger
- RNA-Binding Proteins
- nucleolin
- Proto-Oncogene Proteins c-ret
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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
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