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Pierpaoli E.,Advanced Technology Center for Aging Research | Arcamone A.G.,Naxospharma | Buzzetti F.,Naxospharma | Lombardi P.,Naxospharma | And 2 more authors.
BioFactors | Year: 2013

Breast cancer is the most common malignancy and the most common cause of cancer death in elderly women. Chemoprevention with dietary compounds and their synthetic analogs has emerged as an attractive strategy to prevent carcinogenic progression to invasive cancer. In this study, we investigated the efficacy of some new synthetic derivatives of berberine, a phytochemical isolated from Barberry and other plants, to induce growth arrest of HER-2/neu overexpressing SK-BR-3 breast cancer cells. Supplementation with berberine or with the synthetic derivatives NAX012, NAX013, NAX014, and NAX035 exerted a dose- and time-dependent inhibition of SK-BR-3 cell viability, with a greater effectiveness of NAX012 and NAX014 compounds with respect to berberine. This cytotoxic effect was related to an increased number of apoptotic cells that reached 71.6% and 68.4% after 72 h treatment with 50 μM of NAX012 and NAX014, respectively, compared with 44.2% of berberine. Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21WAF1, p16INK4a, and PAI-1, already after 24 h of 50 μM treatments. Furthermore, berberine, NAX012 and NAX014, all reduced both HER-2/neu expression and phosphorylation on tumor cells, the NAX014 compound showing the higher effectiveness. These results provide novel information on the mechanisms involved in the anticancer effects of berberine and demonstrate the greater effectiveness of NAX012 and NAX014 analogs in inducing apoptosis and cellular senescence in HER-2/neu overexpressing tumor cell lines. © 2013 International Union of Biochemistry and Molecular Biology.

Pierpaoli E.,Advanced Technology Center for Aging Research | Damiani E.,Marche Polytechnic University | Orlando F.,Experimental Animal Models for Aging Unit | Lucarini G.,Marche Polytechnic University | And 7 more authors.
Carcinogenesis | Year: 2015

Berberine (BBR) is a natural isoquinoline alkaloid with proven antiangiogenic and anticancer activities. We recently demonstrated that BBR and its synthetic derivative 13-(4-chlorophenylethyl)berberine iodide, NAX014, exert antiproliferative activity against HER2-overexpressing breast cancer cells, inducing apoptosis, modulating the expression of cell cycle checkpoint molecules involved in cell senescence, and reducing both HER2 expression and phosphorylation on tumor cells. In this study, we examined the anticancer properties of BBR and NAX014 in a transgenic mouse model which spontaneously develops HER2-positive mammary tumors. Repeated intraperitoneal injections of a safety dose (2.5 mg/kg) of NAX014 delayed the development of tumors, reducing both the number and size of tumor masses. In vivo sidestream dark field videomicroscopy revealed a significant lower vessel density in mammary tumors from NAX014-treated mice in comparison with the control group. Immunohistochemical evaluation using CD34 antibody confirmed the reduced vessel density in NAX014 group. Statistically significant increase of senescence associated β-galactosidase and p16 expression, and reduced expression of heparanase were observed in tumors from NAX014-treated mice than in tumors from control animals. Finally, NAX014 treatment decreased the level of perforine and granzyme mRNA in mammary tumors. Berberine did not show any statistically significant modulation in comparison with control mice. The results of the present study indicate that NAX014 is more effective than BBR in exerting anticancer activity delaying the development of mammary tumors in mice transgenic for the HER-2/neu oncogene. The antitumor efficacy of NAX014 is mainly related to its effect on tumor vascular network and on induction of tumor cell senescence. © The Author 2015. Published by Oxford University Press. All rights reserved.

Corsonello A.,Italian National Research Center on Aging | Onder G.,Catholic University of the Sacred Heart | Bustacchini S.,Italian National Research Center on Aging | Provinciali M.,Advanced Technology Center for Aging Research | And 3 more authors.
Drug Safety | Year: 2012

The aging process is characterized by relevant changes in pharmacokinetics. Renal function is known to decline with aging. However, as a result of reduced muscle mass, older individuals frequently have a depressed glomerular filtration rate (GFR) despite normal serum creatinine, and such a concealed renal insufficiency may impact significantly on the clearance of hydrosoluble drugs, as well as the risk of adverse drug reactions (ADRs) from hydrosoluble drugs. The assessment of renal function should thus be a mandatory item in the global examination of patient characteristics. Equations for estimatingGFR have become very popular in recent years. However, different equations may yield significantly different estimated glomerular filtration rate (eGFR) values, which have important implications in dosing drugs cleared by the kidney. Current knowledge suggests that eGFR based on the Chronic Kidney Disease- Epidemiological Collaboration (CKD-EPI) study equation outperformed eGFR based on the Modification of Diet in Renal Disease (MDRD) study equation and creatinine clearance estimate based on the Cockcroft-Gault formula as a predictor of ADRs from kidney cleared drugs. More recently, the combined creatinine-cystatin C equation was shown to perform better than equations based on either of these markers alone in diagnosing CKD, even in older patients. However, its accuracy in predicting ADRs and usefulness in drug dosing is still to be investigated. Adis © 2012 Springer International Publishing AG. All rights reserved.

Viola V.,University of Perugia | Pilolli F.,University of Perugia | Piroddi M.,University of Perugia | Pierpaoli E.,Advanced Technology Center for Aging Research | And 5 more authors.
Genes and Nutrition | Year: 2012

The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (γ and δ) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated "highly metabolized" T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy. © Springer-Verlag 2011.

Cardelli M.,Advanced Technology Center for Aging Research | Marchegiani F.,Advanced Technology Center for Aging Research | Provinciali M.,Advanced Technology Center for Aging Research
Genomics | Year: 2012

The analysis of the genetic variability associated to Alu sequences was hampered by the absence of genome-wide methodologies able to efficiently detect new polymorphisms/mutations among these repetitive elements. Here we describe two Alu insertion profiling (AIP) methods based on the hybridization of Alu-flanking genomic fragments on tiling microarrays. Protocols are designed to preferentially detect active Alu subfamilies. We tested AIP methods by analyzing chromosomes 1 and 6 in two genomic samples. In genomic regions covered by array-features, with a sensitivity of 2% (AIP1) -4% (AIP2) and 5% (AIP1) -8% (AIP2) for the old J and S Alu lineages respectively, we obtained a sensitivity of 67% (AIP1) -90% (AIP2) for the young Ya subfamily. Among the loci showing sample-to-sample differences, 5 (AIP1) -8 (AIP2) were associated to known Alu polymorphisms. Moreover, we were able to confirm by PCR and DNA sequencing 4 new intragenic Alu elements, polymorphic in 10 additional individuals. © 2012 Elsevier Inc.

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