Publications (37) View all
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Article: Induction of endoplasmic reticulum stress response by the indole-3-carbinol cyclic tetrameric derivative CTet in human breast cancer cell lines.
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ABSTRACT: Indole-3-carbinol and its metabolic products are considered promising chemopreventive and anticancer agents. Previously we have shown that the indole-3-carbinol cyclic tetrameric derivative CTet induces autophagy and inhibits cell proliferation via inhibition of Akt activity and overexpression of p21/CDKN1A and GADD45A, in both estrogen receptor-positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines. In the present study, we further characterize the autophagic response and investigate the mechanism through which CTet regulates these events. Analysis of gene expression microarray data and subsequent confirmation by quantitative real-time PCR, showed that CTet is able to induce up-regulation of key signaling molecules involved in endoplasmic reticulum (ER) stress response (e.g. DDIT3/CHOP, CHAC1, ATF3, HSPA5/BiP/GRP78, CEBPB, ASNS) and autophagy (e.g. MAP1LC3B), in both MCF-7 and MDA-MB-231 cell lines. Moreover, the monitoring of Xbp-1 splicing confirmed the activation of IRE1/Xbp-1 ER stress response branch after CTet treatment. The role of autophagic processes (known to be induced by ER stress) was investigated further through ATG5 gene silencing and pharmacological inhibition of AVOs formation. CTet was shown to induce an autophagy-related cell death. Moreover, CTet-treated cells stained with Hoechst/PI revealed the presence of necrotic processes without evidence of apoptosis. The ER stress response was identified as the main upstream molecular mechanism through which CTet acts in both hormone-responsive and triple-negative breast cancer cells. Because of its important role in cancer development, ER stress is a potential target in cancer therapy. The abiltiy of CTet to induce ER stress response and subsequently activate a death program in tumor cells confirms this molecule as a promising anticancer agent.PLoS ONE 01/2012; 7(8):e43249. · 4.09 Impact Factor -
Article: Chemical characterization and source apportionment of fine and coarse particulate matter inside the refectory of Santa Maria Delle Grazie Church, home of Leonardo Da Vinci's "Last Supper".
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ABSTRACT: The association between exposure to indoor particulate matter (PM) and damage to cultural assets has been of primary relevance to museum conservators. PM-induced damage to the "Last Supper" painting, one of Leonardo da Vinci's most famous artworks, has been a major concern, given the location of this masterpiece inside a refectory in the city center of Milan, one of Europe's most polluted cities. To assess this risk, a one-year sampling campaign was conducted at indoor and outdoor sites of the painting's location, where time-integrated fine and coarse PM (PM(2.5) and PM(2.5-10)) samples were simultaneously collected. Findings showed that PM(2.5) and PM(2.5-10) concentrations were reduced indoors by 88 and 94% on a yearly average basis, respectively. This large reduction is mainly attributed to the efficacy of the deployed ventilation system in removing particles. Furthermore, PM(2.5) dominated indoor particle levels, with organic matter as the most abundant species. Next, the chemical mass balance model was applied to apportion primary and secondary sources to monthly indoor fine organic carbon (OC) and PM mass. Results revealed that gasoline vehicles, urban soil, and wood-smoke only contributed to an annual average of 11.2 ± 3.7% of OC mass. Tracers for these major sources had minimal infiltration factors. On the other hand, fatty acids and squalane had high indoor-to-outdoor concentration ratios with fatty acids showing a good correlation with indoor OC, implying a common indoor source.Environmental Science & Technology 11/2011; 45(24):10344-53. · 4.80 Impact Factor -
Article: Breast change perception in women after smoking cessation. A pilot study.
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ABSTRACT: There are several barriers to smoking cessation that are unique to women. Compared to men, women report lower levels of motivation to quit and greater perceived difficulty with cessation. However, recent studies might favor commitment by women to quit through higher risk perception related e.g. to the development of premature facial wrinkling or the decrease in mammographic density due to cigarette smoking. A pilot study to evaluate the perception of breast change after cessation and its possible motivational effect on maintenance was carried out. We interviewed 25 premenopausal women who had quit ≥1 year before. We obtained information from the women and discussed changes in breast size and fullness. The two groups of women with and without breast change were statistically compared using the nonparametric Mann-Whitney test (continuous variables) and the Fisher test (categorical variables). Median age was 41 years (range, 30-49 years). Median carbon monoxide (CO) before quitting was 18 ppm and median pack years (PY) was 22.5; both parameters characterize a category of mild smokers. Sixteen women (64%) reported breast changes 6 months after quitting smoking. This outcome was paralleled by only moderate effects on weight or body mass index (BMI) increase after quitting. Notably, of the 16 women with breast change, only 3 (19%) with a normal baseline BMI showed a BMI increase to >25. Within the limitations of the small size of a pilot study, these results indicate that premenopausal women experience subjective perception of change in breast size after smoking cessation, which may not be totally explained by weight gain. Further studies are needed to understand the effect, if any, of such perception on the motivation to quit smoking.Tumori. 09/2011; 97(5):672-5. -
Article: The indole-3-carbinol cyclic tetrameric derivative CTet inhibits cell proliferation via overexpression of p21/CDKN1A in both estrogen receptor-positive and triple-negative breast cancer cell lines.
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ABSTRACT: Indole-3-carbinol (I3C), an autolysis product of glucosinolates present in cruciferous vegetables, and its dimeric derivative (3,3'-DIM) have been indicated as promising agents in preventing the development and progression of breast cancer. We have recently shown that I3C cyclic tetrameric derivative CTet formulated in γ-cyclodextrin (γ-CD) efficiently inhibited cellular proliferation in breast cancer cell lines. This study aims to analyze the mechanisms involved in the in vitro inhibition of cell proliferation and to evaluate the in vivo antitumor activity of CTet in a xenograft study. Estrogen receptor-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines were exposed to CTet to evaluate cell cycle perturbation (propidium iodide staining and cytofluorimetric acquisition), induction of autophagic morphological features (co-localization of LC3b autophagosome marker and LAMP2a lysosome marker by immunofluorescence) and changes in protein expression (immunoblot and microarray-based gene expression analyses). To test the in vivo efficacy of CTet, female athymic nude mice inoculated with MCF-7 cells were i.p. treated with 5 mg/kg/day of CTet for five days/week for two weeks and the tumor mass was externally monitored. CTet induced accumulation in G2/M phase without evidence of apoptotic response induction in both cell lines tested. In triple-negative MDA-MB-231 the autophagic lysosomal activity was significantly up-regulated after exposure to 4 μM of CTet for 8 hours, while the highest CTet concentration was necessary to observe autophagic features in MCF-7 cells. The inhibition of Akt activity and p53-independent p21/CDKN1A and GADD45A overexpression were identified as the main molecular events responsible for CTet activity in MCF-7 and p53-mutant MDA-MB-231 cells. In vivo, CTet administration was able to significantly inhibit the growth of MCF-7 xenotransplanted into nude mice, without adverse effect on body weight or on haematological parameters. Our data support CTet formulated with γ-CD as a promising and injectable anticancer agent for both hormone-responsive and triple-negative breast tumors.Breast cancer research: BCR 03/2011; 13(2):R33. · 5.24 Impact Factor -
Article: Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma.
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ABSTRACT: Our aim was to assess the activation profile of EGFR, PDGFRB and PDGFRA receptor tyrosine kinases (RTK) and their downstream effectors in a series of cryopreserved diffuse malignant peritoneal mesothelioma (DMPM) surgical specimens to discover the targets for drug inhibition. We also made a complementary analysis of the cytotoxic effects of some kinase inhibitors on the proliferation of the human peritoneal mesothelioma STO cell line. We found the expression/phosphorylation of EGFR and PDGFRB in most of the tumours, and PDGFRA activation in half. The expression of the cognate ligands TGF-α, PDGFB and PDGFA in the absence of RTK mutation and amplification suggested the presence of an autocrine/paracrine loop. There was also evidence of EGFR and PDGFRB co-activation. RTK downstream signalling analysis demonstrated the activation/expression of ERK1/2, AKT and mTOR, together with S6 and 4EBP1, in almost all the DMPMs. No KRAS/BRAF mutations, PI3KCA mutations/amplifications or PTEN inactivation were observed. Real-time polymerase chain reaction revealed the decreased expression of TSC1 c-DNA in half of the tumours. In vitro cytotoxicity studies showed the STO cell line to be resistant to gefitinib and sensitive to sequential treatment with RAD001 and sorafenib; these findings were consistent with the presence of the KRAS mutation G12D in these cells although it was not detectable in the original tumour. Our results highlight the ligand-dependent activation and co-activation of EGFR and PDGFRB, as well as a connection between these activated RTKs and the downstream mTOR pathway, thus supporting the role of combined treatment with RTK and mTOR inhibitors in DMPM.European journal of cancer (Oxford, England: 1990) 10/2010; 46(15):2837-48. · 4.12 Impact Factor
