Biomedical subjects

Patrizia Gazzerro

Publications and source records attributed to Patrizia Gazzerro.

8 recordsLinked to original sources

PubMed2007

Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy.

Endocannabinoids are now emerging as suppressors of key cell-signaling pathways involved in cancer cell growth, invasion, and metastasis. We have previously observed that the metabolically stable anandamide analog, 2-methyl-2'-F-anandamide (Met-F-AEA) can inhibit the growth of thyroid cancer in vivo. Our hypothesis was that the anti-tumor effect observed could be at least in part ascribed to inhibition of neo-angiogenesis. Therefore, the aim of this study was to assess the anti-angiogenic activity of Met-F-AEA, to investigate the molecular mechanisms underlying this effect and whether Met-F-AEA could antagonize tumor-induced endothelial cell sprouting. We show that Met-F-AEA inhibited bFGF-stimulated endothelial cell proliferation, in a dose-dependent manner, and also induced apoptosis, both effects reliant on cannabinoid CB1 receptor stimulation. Analyzing the signaling pathways implicated in angiogenesis, we observed that the bFGF-induced ERK phosphorylation was antagonized by Met-F-AEA, and we found that p38 MAPK was involved in Met-F-AEA-induced apoptosis. Moreover, Met-F-AEA was able to inhibit bi-dimensional capillary-like tube formation and activity of matrix metalloprotease MMP-2, a major matrix degrading enzyme. Importantly, we demonstrated that Met-F-AEA is also functional in vivo since it inhibited angiogenesis in the chick chorioallantoic neovascularization model. Finally, Met-F-AEA inhibited tumor-induced angiogenesis in a three-dimensional model of endothelial and thyroid tumor cell (KiMol) spheroids co-cultures in different 3-D polymeric matrices that resemble tumor microenvironment and architecture. Thus, our results suggest that anandamide could be involved in the control of cancer growth targeting both tumor cell proliferation and the angiogenic stimulation of the vasculature.

Angiogenesis Inhibitors↗

PubMed2006

HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway.

The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced activation of the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemistry showed an increased number of proliferating cell nuclear antigen (PCNA)-positive cells in the thyroid gland of PTU-treated rats. Moreover, the phosphorylation of ERK1 and ERK2 was increased in the extract from goiter tissue as compared with the thyroid tissue of untreated rats. To determine whether the inhibition of selected pro-survival pathways (i.e., p21ras-MAPK) was sufficient to affect goitrogenesis, thyroids from 12 PTU-treated rats were injected in vivo with an adenovirus transducing a dominant-negative ras gene (Rad-L61.S186) and another set of 12 rats were injected with a pharmacological inhibitor of MAPK (PD98059). Both Rad-L61.S186 and PD98059 were able to inhibit the PTU-induced goiter. It is interesting to note that lovastatin, when administered in drinking water, significantly prevented the thyroid gland enlargement. Therefore, lovastatin-treated thyroid glands were significantly smaller than those treated with PTU alone. In addition, the lovastatin-treated glands also showed a decreased expression of phosphorylated ERK1/2 and a number of PCNA-positive cells. Our data suggest that lovastatin is an efficient inhibitor of goitrogenesis and provide a rationale for innovative therapeutic strategies employing statins in the treatment of nodular goiter in humans.

Animals↗

PubMed2006

The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism.

The endocannabinoid system has been shown to modulate key cell-signaling pathways involved in cancer cell growth. In this study, we show that cannabinoid receptor type 1 (CB1) antagonist Rimonabant (SR141716) inhibited human breast cancer cell proliferation, being more effective in highly invasive metastatic MDA-MB-231 cells than in less-invasive T47D and MCF-7 cells. The SR141716 antiproliferative effect was not accompanied by apoptosis or necrosis and was characterized by a G1/S-phase cell cycle arrest, decreased expression of cyclin D and E, and increased levels of cyclin-dependent kinase inhibitor p27KIP1. We have also shown that SR141716 exerted a significant antiproliferative action, in vivo, by reducing the volume of xenograft tumors induced by MDA-MB-231 injection in mice. On the other hand, at the concentration range in which we observed the antiproliferative effect in tumor cells, we did not observe evidence of any genotoxic effect on normal cells. Our data also indicate that the SR141716 antiproliferative effect requires lipid raft/caveolae integrity to occur. Indeed, we found that CB1 receptor (CB1R) is completely displaced from lipid rafts in SR141716-treated MDA-MB-231 cells, and cholesterol depletion by methyl-beta-cyclodextrin strongly prevented SR141716-mediated antiproliferative effect. Taken together, our results suggest that SR141716 inhibits human breast cancer cell growth via a CB1R lipid raft/caveolae-mediated mechanism.

Animals↗

PubMed2006

Cannabinoids and cancer: pros and cons of an antitumour strategy.

In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called 'endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiproliferative actions of cannabinoid agonists on several tumour cells in vitro and in animal models. In this article, we will review the principal molecular pathways modulated by cannabinoids on cancer and summarize pros and cons evidence on the possible future use of endocannabinoid-based drugs in cancer therapy.

Animals↗

PubMed2005

Modulation of RIZ gene expression is associated to estradiol control of MCF-7 breast cancer cell proliferation.

The retinoblastoma protein-interacting zinc-finger (RIZ) gene, a member of the nuclear protein methyltransferase superfamily, is characterized by the presence of the N-terminal PR domain. The RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the PR (PRDI-BF1 and RIZ homologous) domain, RIZ2 lacks it. RIZ gene expression is altered in a variety of human cancers and RIZ1 is now considered to be a candidate tumor suppressor. Estradiol treatment of MCF-7 cells produced a selective decrease of RIZ1 transcript and an increase of total RIZ mRNA. Experiments of chromatin immunoprecipitation indicated that RIZ2 protein expression was controlled by estrogen receptor and RIZ1 had a direct repressor function on c-myc gene expression. To investigate the role of RIZ gene products as regulators of the proliferation/differentiation transition, we analyzed the effects of forced suppression of RIZ1 induced in MCF-7 cells by siRNA of the PR domain-containing form. Silencing of RIZ1 expression stimulated cell proliferation, similar to the effect of estradiol on these cells, associated with a transient increase of c-myc expression.

Breast Neoplasms↗

PubMed2005

Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cells.

In this report we show, by confocal analysis of indirect immunofluorescence, that the type-1 cannabinoid receptor (CB1R), which belongs to the family of G-protein-coupled receptors, is expressed on the plasma membrane in human breast cancer MDA-MB-231 cells. However, a substantial proportion of the receptor is present in lysosomes. We found that CB1R is associated with cholesterol- and sphyngolipid-enriched membrane domains (rafts). Cholesterol depletion by methyl-beta-cyclodextrin (MCD) treatment strongly reduces the flotation of the protein on the raft-fractions (DRM) of sucrose density gradients suggesting that CB1 raft-association is cholesterol dependent. Interestingly binding of the agonist, anandamide (AEA) also impairs DRM-association of the receptor suggesting that the membrane distribution of the receptor is dependent on rafts and is possibly regulated by the agonist binding. Indeed MCD completely blocked the clustering of CB1R at the plasma membrane. On the contrary the lysosomal localization of CB1R was impaired by this treatment only after AEA binding.

Arachidonic Acids↗

PubMed2004

The Zn-finger domain of RIZ protein promotes MCF-7 cell proliferation.

In order to understand the oncogenic properties of retinoblastoma-interacting zinc-finger (RIZ) gene products, we produced an MCF-7-derived cell line expressing a fusion protein containing the zinc-finger (aa 359-497) domain of RIZ protein (MCF-7/znf). The Zn-finger domain contains three of the eight putative Zn-finger motifs and is located in proximity of the E1A-like domain containing the Rb protein-binding motif. The MCF-7/znf cells showed a higher growth rate than the parental or the control cell lines, both in hormone-deprived conditions or upon estrogen stimulation. Furthermore, they were less sensitive to the growth inhibitory effect of anti-estrogens and showed a higher level of expression of cyclin D1 and A. The expressed Zn-finger domain recombinant product was localized in the nucleus and in the nucleoli and its expression modified the pattern of actin staining in the cytoplasm. In conclusion the presented results indicated that the Zn-finger domain could be endowed with the putative oncogenic activity of RIZ2 gene product.

Breast Neoplasms↗

PubMed2002

Cytokine pattern in postmenopause.

OBJECTIVE: The present study was undertaken to evaluate the pattern of serum cytokine production in postmenopausal women and the relationship with the hormonal status. A group of fertile women served as controls. METHODS: Eighty-two women in apparent good health, non-smokers and without a history of hormone replacement therapy, were enrolled for the study. The women were divided in two groups according to their hormonal status: fertile women (n=34, age 32 +/- 7 years) and postmenopausal women (n=48, age 54 +/- 8 years). Blood samples were withdrawn in the morning, after an overnight fast. RESULTS: Sex hormones (LH, FSH, Estradiol, Progesterone, DHEA, DHEA-S), as well as GH and IGF-1 levels, were significantly higher in the serum of fertile women as compared with their postmenopausal counterparts. Unlike IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, significant differences were observed in serum IL-6, IL-18, TNFalpha and TNFbeta between groups: both IL-6 and IL-18 were higher in postmenopausal women, while TNFalpha and TNFbeta were significantly lower. There was an inverse relationship between serum DHEA and DHEA-S levels and both IL-6 (r= -0.46, P<0.02) or IL-18 (r= -0.38, P<0.05) serum concentrations. CONCLUSIONS: Compared with fertile counterparts, women in postmenopause present an alteration in serum cytokine profile suggesting a prevalence of Th2 lymphocytes.

Adolescent↗