Search

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-α 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.

Numerous studies investigated the effects of pharmacological doses of DHEA in animals. Among protective effects, antiglucocorticoid potencies, triggering and modulation of immunity and anticancerous effects were reported. Because DHEA levels decrease in aging humans, this steroid has been assayed as replacement therapy in elderly volunteers without striking evidence for beneficial effects. Examination of the investigations carried out in animals lead to suspect that, rather than DHEA, its metabolites produced in tissues could be responsible for some of the observed effects. Known as the 'mother steroid', DHEA is a precursor for androgenic and estrogenic steroid hormones. In addition, DHEA is hydroxylated at the 7α position by the cytochrome P450 7B1 (CYP7B1), and the 7α-hydroxy-DHEA produced is a substrate for the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts it into 7β-hydroxy-DHEA. Both 7-hydroxylated metabolites were shown to favor the onset of immunity in mice and the activation of memory T cells in humans. Other DHEA and testosterone-derived metabolites, namely epiandrosterone and 5α-androstane-3β,17β-diol, are also substrates for the CYP7B1 and their 7α-hydroxylated products were also converted into the 7β epimer by the 11β-HSD1. When assayed at doses 104 lower than DHEA, 7β-hydroxy-epiandrosterone was shown to shift the prostaglandin metabolism patterns from prostaglandin E2 (PGE2) to PGD2 production, thus triggering the resolution of inflammation. In addition, 7β-hydroxy-epiandrosterone (1 nM) exerted the same effects as tamoxifen (1 μM) on the proliferation of MCF-7 and MDA-231 human breast cancer cells. These findings suggest that the observed effects of 7β-hydroxy-epiandrosterone could be mediated by estrogen receptors. This overview of recent research implies that DHEA does not act directly and that its effects are due to its metabolites when produced in tissues. Treatments with DHEA should take into account the target tissue abilities to produce the desired metabolites through the two key enzymes, CYP7B1 and 11β-HSD1. [ABSTRACT FROM AUTHOR]

Numerous studies investigated the effects of pharmacological doses of DHEA in animals. Among protective effects, antiglucocorticoid potencies, triggering and modulation of immunity and anticancerous effects were reported. Because DHEA levels decrease in aging humans, this steroid has been assayed as replacement therapy in elderly volunteers without striking evidence for beneficial effects. Examination of the investigations carried out in animals lead to suspect that, rather than DHEA, its metabolites produced in tissues could be responsible for some of the observed effects. Known as the 'mother steroid', DHEA is a precursor for androgenic and estrogenic steroid hormones. In addition, DHEA is hydroxylated at the 7α position by the cytochrome P450 7B1 (CYP7B1), and the 7α-hydroxy-DHEA produced is a substrate for the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts it into 7β-hydroxy-DHEA. Both 7-hydroxylated metabolites were shown to favor the onset of immunity in mice and the activation of memory T cells in humans. Other DHEA and testosterone-derived metabolites, namely epiandrosterone and 5α-androstane-3β,17β-diol, are also substrates for the CYP7B1 and their 7α-hydroxylated products were also converted into the 7β epimer by the 11β-HSD1. When assayed at doses 104 lower than DHEA, 7β-hydroxy-epiandrosterone was shown to shift the prostaglandin metabolism patterns from prostaglandin E2 (PGE2) to PGD2 production, thus triggering the resolution of inflammation. In addition, 7β-hydroxy-epiandrosterone (1 nM) exerted the same effects as tamoxifen (1 μM) on the proliferation of MCF-7 and MDA-231 human breast cancer cells. These findings suggest that the observed effects of 7β-hydroxy-epiandrosterone could be mediated by estrogen receptors. This overview of recent research implies that DHEA does not act directly and that its effects are due to its metabolites when produced in tissues. Treatments with DHEA should take into account the target tissue abilities to produce the desired metabolites through the two key enzymes, CYP7B1 and 11β-HSD1. [ABSTRACT FROM AUTHOR]

Inflamed tissues produce both prostaglandins (PGs) and 7α-hydroxylated derivatives of native circulating 3β-hydroxysteroids. These 7α-hydroxysteroids are in turn transformed into 7β-hydroxylated epimers by 11β-hydroxysteroid dehydrogenase type 1 in the tissue. 7β-Hydroxy-epiandrosterone (7β-hydroxy-EpiA) affects PG production in two models of inflammation, dextran sodium sulfate-induced colitis in the rat and TNF-α-induced activation of PG production and PG synthase expression in cultured human peripheral blood monocytes (hPBMC). Treatment with 7β-hydroxy-EpiA led to a shift from high to low colonic PGE2 levels and from low to high 15-deoxy-Δ12-14-PGJ2 (15d-PGJ2) levels, together with changes in the expression of the respective PG synthases and resolution of colonic inflammation. Addition of 7β-hydroxy-EpiA to hPBMC also changed the expression of PG synthases and decreased PGE2 while increasing 15d- PGJ² production. These effects were only observed with 7β-hydroxy-EpiA and not with 7α-hydroxy- or 7bhydroxy- dehydroepiandrosterone (7α-hydroxy-DHEA and 7β-hydroxy-DHEA). 15d-PGJ2, which is the native ligand for peroxisome proliferator-activated receptor subtype g, contributes to cell protection and to the resolution of inflammation. Our results therefore suggest that 7β-hydroxy-EpiA may facilitate inflammatory resolution by shifting PG production from PGE2 to PGD2 and 15d-PGJ2. The finding that 7β-hydroxy-EpiA was effective at nM concentrations, whereas the two structurally closely related hydroxysteroids 7α-hydroxy-DHEA and 7β-hydroxy-DHEA were inactive suggests that the effects of 7β-hydroxy-EpiA are specific to this steroid and may be mediated by a specific receptor. [ABSTRACT FROM AUTHOR]

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 anchorageindependent 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-a 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. [ABSTRACT FROM AUTHOR]