Recent studies have shown that HDAC inhibitors act synergistically with camptothecin derivatives in combination therapies. To exploit this synergy, new hybrid molecules targeting simultaneously topoisomerase I and HDAC were designed. In particular, a selected multivalent agent containing a camptothecin and a SAHA-like template showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.
BackgroundHyaluronic acid (HA)-based devices are among the most popular filler agents for skin rejuvenation. One of the principal goals is the improvement in residence time of HA-based products, to increase their performance and reduce frequency of the treatment. So, understanding fillers, behavior after subcutaneous injection is a fundamental aspect for discovery and optimization of new products. Current in vivo approaches to detect/quantify injected HA fillers are not always well optimized or easy to apply.ObjectiveTo develop more efficacious and noninvasive diagnostic tools to make a quantitative evaluation of the degradation of fillers in a small animal model.Materials and methodsWe evaluated the residence time of different HA-based fillers, fluorescein-labeled and not, injected subcutaneously in mice. Volumes of fillers were monitored through high-frequency ultrasound (HF-US) method while fluorescence intensity through the well-established fluorescence living imaging method. To confirm the effectiveness of HF-US, obtained volumetric measurements were compared with fluorescence intensity values.ResultsBoth the presented methods revealed the same degradation kinetics for the tested products.ConclusionThe two used methods are fully comparable and quantitatively accurate. The presented approach has been proved to be noninvasive, sensitive, and reproducible.
sonographic evaluation revealed large omphalocele probably with liver involvement. Also it was observed acrania and anencephaly. Fetal chorion villus sampling (CVS) was performed that showed Trisomy 18. In rare cases of Trisomy 18 fetal concominant anencephaly and large omphalocele could be observed.
Acetylation is emerging as a major form of post-translational regulation of gene expression beyond histones and the maintenance of chromatin. Acetylation has been found to play a role in many cellular functions including DNA repair, cell division, apoptosis, cell signaling, chaperone activity and in the cytoskeleton. It is now evident that, given the pleiotropic effects of HDAC inhibitors (HDACi), their therapeutic potential is expected to be best exploited through combination with other antitumor agents . Indeed preclinical data with several tumor cell lines have shown synergistic effects when combining HDACi with various DNA damaging agents, suggesting their involvement in the modulation of DNA damage response (Munshi et al. Clin Cancer Res (2005) 11: :4912-4922; Chen et al. Cancer Res 2007, 67: 5318-5327).To increase our understanding on the molecular and pharmacological properties of ST3595 (Zuco et al. PLoS ONE,2011, 6(12)), a novel Pan- HDACs inhibitor, we have investigated its role in modulating the DNA-repair genes expression and how this modulation could eventually be translated into a therapeutical approach. Our studies evidentiated that, besides the modulation of typical pathways associated to HDAC inhibition (i.e. cell cycle control, DNA replication, apoptosis, cell differentiation, etc.) and mainly mediated by acetylation of histones, ST3595 strongly induces the modulation of molecular markers associated with DNA-damage signalling (γ-H2A.X, acetyl-p53Lys373/382, p-Chk1/2, etc.), p53- signalling and response pathways (i.e. MDM2, Bax, Noxa, PUMA, p21, etc.), and ER-stress response (gadd-153, ATF-3, ATF-4, Grp78, Grp34, HERPUD1 et others), in several tumour models. In addition, an extensive TaqMan gene expression analysis in ST3595-treated tumour cells, revealed several target genes, including ATM, gadd45-α, gadd45-β, and some repair enzymes, modulated directly or indirectly by this molecule. Since PARP-1 acts as a DNA damage sensor and has been implicated in multiple DNA repair pathways, including the SSB, DSB, and base excision repair (BER) pathways, we tested ST3595 as putative PARP inhibitor. In these experiments, although ST3595 have a mild direct effect against the enzyme, a very strong inhibitory effect (at low μM dose) was measured in vitro, by means of a specific Poly-ADP-ribosylation (parylation) assay, on HeLa cells. To assess the specificity and the therapeutical relevance of this observation, we investigated the efficacy of ST3595 in two breast cancer models, MDA MB436 (triple negative, BRCA1/2 mutated) compared to MDA MB231 (triple negative). The results from in vitro and in vivo experiments have shown an increased antitumor activity of ST3595 against BRCA1/2 mutated tumor and cured mice, when the drug has been associate to Cisplatin. Citation Format: Claudio Pisano, Marcella Barbarino, Francesca De Paolis, Giorgia Pollastrone, Ilaria Laporta, Assunta Riccio, Alfonsina Porciello, Loredana Vesci, Carmela Melito, Ferdinando Milazzo, Pasquale Deluca. Pan HDACs inhibitor ST3595 targets PARP activity and has curative effect in breast BRCA-deficient model when combined with cisplatin treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1012. doi:10.1158/1538-7445.AM2013-1012
Mesothelioma, sometimes referred to as asbestos cancer, is known to be among the most aggressive and difficult to treat tumours. The disease attacks the mesothelium, a protective two-layered membrane that covers the internal organs of the body including the lungs, heart and abdominal organs. Mesothelioma can affect any of these layers, but is usually seen in the pleural (lung) or peritoneal (abdomen) mesothelium. The most commonly diagnosed form of this cancer is pleural mesothelioma, caused primarily by the inhalation of asbestos fibers. The prevalence of this cancer is estimated at less than 1% of all cancers, however its incidence is increasing, with an expected peak in the next 10-20 years. Mesotheliomas are tumours that have a poor prognosis due to limited treatment options. The most aggressive form is the sarcomatoid histotype, followed by the biphasic and the epithelioid histotypes.In order to setup in vivo models of human mesothelioma, translational related to human pathology in terms of histology, antigen expression and pharmacological response to therapy, we have established three mesothelioma in vivo models using primary cells derived from patients having different mesothelioma histotypes.We stably transfected MM-432 (sarcomatoid), MM-473 (epithelioid) and MM-487 (biphasic) mesothelioma cell lines with a luciferase expression vector. The selected high luc-espressing clones were inoculated intrapleurally in immunodeficient nude mice, and they successfully invaded and proliferated within the murine host. In particular, the epithelioid histotype presented tumour growth 100% of the time, after a short latency period. The biphasic histotype failed to present tumour growth in 30% of the cases, however was far more aggressive than the epithelial histotype upon establishment of tumour growth. Moreover, the ex-vivo Immunocytochemistry (i.e for CEA, EMA, Mesothelin, Podoplanin, calretinin) and biochemical characterization (i.e.EGFR, VEGF, Top1, TKs pathways) of the three histotypes, revealed histotype-related differences. Finally, the cytotoxic responses to a panel of antitumor drugs (i.e . Doxorubicin , Topotecan , Ciclofosfamide, Dacarbazina, Gemcitabine, Temozolomide, Bortezomib, 5-azacitidina, Paclitaxel, Etoposide, 5-FU, Cisplatin, and AZD-2281) revealed that the three original cell lines, compared to the corresponding luc-expressing clones, had similar sensitivities to drugs depending upon the tumor histotypes. Further, in vivo characterizations focused on chemotherapeutic responses of these models, are currently in progress. Citation Format: Claudio Pisano, Alison G. Cole, Marcella Barbarino, Erminia Bianchino, Mario Guglielmi, Carmela Melito, Grazia Mercadante, Alfonsina Porciello, Assunta Riccio, Ilaria La Porta, Sara Orecchia, Roberta Libener, Laura Mazzucco, Simonetta Andrea Licandro, Pasquale De Luca. Mice models of three human mesothelioma histotypes derived from primary patient tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5556. doi:10.1158/1538-7445.AM2014-5556
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