63,752 research outputs found
Small molecule inhibitors of kdm5 histone demethylases increase the radiosensitivity of breast cancer cells overexpressing JARID1B
No full textNHERF1 (Na+/H+ exchanger 3 regulating factor 1) is an integral membrane adaptor protein carrying two NH2-terminal PDZ (postsynaptic density 95/discs large/zona occludens 1) tandem domains.1 PDZ1 (11-97 amino acids) and PDZ2 (150-237 amino acids) show 74% identity to each other and bind to specific carboxyl-terminal motifs on target proteins, such as -catenin and PTEN, that may have a pivotal role in tumorigenesis. Oncogenic activity of NHERF1 is strictly dictated by changes on its subcellular localization.1,2 A pharmacophore model was used to filter out an in-house training set of about 6000 compounds, leading to identify a potent inhibitor of NHERF1.3 We herein reported the design and synthesis of new NHERF1 inhibitors (Figure 1).4 The new compounds were synthesized by treating the appropriate indole with thionyl chloride and the proper amino derivative in the presence of pyridine in dichloromethane at room temperature for 12 h; alternatively, the coupling reaction was carried out using (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and triethylamine in N,N-dimethylformamide at room temperature for 12 h. Compounds 5, 9, 10 and 13 exhibited a remarkable cytotoxicity in Ls174TshBeta-Cat cells. The binding to NHERF1 PDZ was confirmed by means of a dansylated peptide corresponding to the C-terminal sequence of Beta2-AR. When used in combination with antagonists of Beta-catenin, the new derivatives increased the apoptotic death of colorectal cancer cells refractory to currently available Wnt/Beta-catenin-targeted agents. References 1. Vaquero, J.; Nguyen Ho-Bouldoires, T. H.; Clapéron, A.; Fouassier, L. Oncogene 2017, 36, 3067‒3079. 2. Georgescu, M. M.; Morales, F. C.; Molina, J. R.; Hayashi, Y. Curr. Mol. Med. 2008, 8, 459−468. 3. Saponaro, C.; Sergio, S.; Coluccia, A.; De Luca, M.; La Regina, G.; Mologni, L.; Famiglini, V.; Naccarato, V.; Bonetti, D.; Gautier, C.; Gianni, S.; Vergara, D.; Salzet, M.; Fournier, I.; Bucci, C.; Silvestri, R.; Gambacorti Passerini, C.; Maffia, M.; Coluccia, A. M. L. Oncogene 2018, 37, 3301‒3316. 4. Coluccia, A.; La Regina, G.; Naccarato, V.; Nalli, M.; Orlando, V.; Biagioni, S.; De Angelis, M. L.; Baiocchi, M.; Gautier, C.; Gianni, S.; Di Pastena, F.; Di Magno, L.; Canettieri, G.; Coluccia, A. M. L.; Silvestri, R. ACS Med. Chem. Lett. 2019, 10, 499‒503
Lessico Etimologico Italiano. Supplemento bibliografico, a cura di M Pfister, con la collaborazione di R. Coluccia, D. Hauck, H. Hauck, G. Tancke. Analisi, progettazione informatica ed elaborazione dati a cura di M. Linciano, Wiesbaden, Reichert
No full textTreating chronic myeloid leukemia by inhibition of tubulin polymerization
No full textMicrotubules are an attractive target for the development of active anti-leukemia agents (1). Despite some evidence, the therapeutic potential of colchicine site binding agents in chronic myeloid leukemia (CML) has not been adequately explored.
Recently, starting from previously reported aroylindoles (ARIs, e.g. 1) we have developed 3-aroyl-1-arylpyrroles (ARAPs, e.g. 2) via benzocracking approach (Chart 1) (2). Pursuing our studies, we designed and synthesized 3-aroyl-1,4-diarylpyrroles (ARDAPs, 3-16) as potential anticancer agents (3).
ARDAPs exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. (4-(4-Aminophenyl)-1-phenyl-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from CML patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. The same compound minimally affected the proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. New ARDAP significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via mitochondria-dependent pathway and increased the cytotoxic effects of IM in human CML cells.
References. (1) Yeh, Y.-Y.; Liou, J.-P.; Lee, Y.-L. et al. Invest. New Drugs 2017, 35, 427-435. (2) La Regina, G.; Bai, R.; Coluccia, A. et al. J. Med. Chem. 2014, 57, 6531-6552. (3) La Regina, G.; Bai, R.; Coluccia, A. et al. ACS Med. Chem. Lett. 2017, 8, 521-526
Cytogenetic analysis of the Mediterranean Palinuridae Palinurus elephas and P. mauritanicus (Crustacea, Decapoda).
No full textCytogenetic analysis of the Mediterranean Palinuridae Palinurus elephas and P. mauritanicus (Crustacea, Decapoda)
E. Coluccia, A. Cau, S. Salvadori, R. Cannas, A.M. Deiana
Dipartimento di Biologia Animale ed Ecologia, Università di Cagliari, V.le Poetto, 1- 09126 Cagliari, Italy - email: [email protected]
Palinurus elephas (Fabricius, 1787) and P. mauritanicus Gruvel, 1911 are two Mediterranean spiny lobster species living at different depths.. The knowledge on the karyology of Decapoda are scanty owing to technical constraints in obtaining good chromosomal preparations. To date cytogenetic analysis by chromosome banding are very few. In the contest of a cytogenetic and molecular study on the two Mediterranean Palinuridae we present a characterization of mitotic and meiotic chromosomes of these species by different staining techniques. Chomosomal preparations have been obtained from testicular and somatic tissues by a direct method. Heterochromatin has been localized by C-banding. This technique allowed also a sharp differentiation of chromosomes, a clear identification of meiotic figures and the detection of supernumerary chromosomes in both species. B chromosomes are variable in number, very small, completely heterochromatic and in meiosis I they are often asynaptic. Their presence could account for the variability recorded in determining the chromosome number. The heterochromatin analysis has been deepened by fluorochrome banding. Quinacrine and DAPI localized AT-rich clusters in several centromeric and paracentromeric regions; chromomicin A3 localized GC-rich DNA in centromeric and paracentromeric regions and in some small chromosomes, entirely fluorescent
Forestierismi nell’italiano della sostenibilità
No full textLa parola sostenibilità richiama concetti eterogenei, progressivamente elaborati. Negli ultimi decenni, ha assunto un valore che abbraccia aspetti economici, sociali e ambientali della gestione delle risorse, efficienza energetica, bioeconomia, mobilità, produzione dei beni e cambiamenti climatici.
Parole e locuzioni dell’italiano “sostenibile” descrivono, analizzano e affrontano le questioni legate alla capacità di un sistema (sia esso un ecosistema, un’impresa o una comunità) di mantenere le proprie componenti in equilibrio e di preservare la propria capacità di funzionare nel tempo, tutelando così i bisogni delle generazioni future. Il lessico che veicola questi contenuti si caratterizza per essere ricco di neologismi (per le continue evoluzioni e innovazioni introdotte) e di forestierismi (in virtù della rete di comunicazione internazionale che globalmente affronta le sfide ambientali)
3-Aroyl-1,4-diarylpyrroles inhibit chronic myeloid leukemia cell growth through an interaction with tubulin
No full textMicrotubules are an attractive target for the development of effective anti-leukemia agents.[1] Evidence has accumulated correlating inhibition of tubulin polymerization and leukemic cell proliferation.[2] The activity of colchicine site agents in chronic myeloid leukemia (CML) has not been adequately explored.
Recently, starting from previously reported aroylindoles (ARI, 1)[3] we developed a class of 3-aroyl-1-arylpyrroles (ARAPs, 2) via benzocracking approach by shifting the indole benzene moiety to position 1 of the pyrrole ring.[4] ARAPs proved to be potent inhibitors of both tubulin assembly and cancer cells growth, by binding the colchicine binding site. Pursuing our studied on tubulin targeting agents, we designed 3-aroyl-1,4-diarylpyrroles (ARDAPs, 3-16) as potential anticancer agents bearing different substituents at the 1- or 4-phenyl ring (Chart 1).
ARDAPs exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. (4-(4-Aminophenyl)-1-phenyl-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from CML patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. The same compound minimally affected the proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. New ARDAP significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria-dependent pathway and increased the cytotoxic effects of IM in human CML cells.
References. [1] de Bruin, E. C.; Medema, J. P. Cancer Treat. Rev. 2008, 34, 737-749. [2] Bates, D.; Feris, E. J.; Danilov, A. V. et al. Cancer Biol. Ther. 2016, 17, 291-299. [3] La Regina, G.; Sarkar, T.; Bai, R. et al. J. Med. Chem. 2009, 52, 7512-7527. [4] La Regina, G.; Bai, R.; Coluccia, A. et al. J. Med. Chem. 2014, 57, 6531-6552
Design, synthesis and biological evaluation of PDZ1 targeting NHERF1 inhibitors as anticancer agents
No full textKDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair.1 These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance.2,3 For these reasons, these enzymes are potential therapeutic targets. In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B.4 In particular, compounds RS3195, RS3152, RS3183, RS5033 and RS4995 were assayed in terms of H3K4 demethylation (western blot), radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation) (Figure 1). We showed that three compounds can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. These findings confirmed the involvement of H3K4 specific demethylases in the response to DNA damage, showed a requirement of the catalytic function and suggested new strategies for the therapeutic use of their inhibitors. References 1. Blair, L. P.; Cao, J.; Zou, M. R.; Sayegh, J.; Yan, Q. Cancers 2011, 3, 1383–1404. 2. Xiang, Y.; Zhu, Z.; Han, G.; Ye, X.; Xu, B.; Peng, Z.; Ma, Y.; Yu, Y.; Lin, H.; Chen, A. P.; Chen, C. D. Proc. Natl. Acad. Sci. USA 2007, 104, 19226–19231. 3. Zeng, J.; Ge, Z.; Wang, L.; Li, Q.; Wang, N.; Bjorkholm, M.; Jia, J.; Xu, D. Gastroenterology 2010, 138, 981–992. 4. Pippa, S.; Mannironi, C.; Licursi, V.; Bombardi, L.; Colotti, G.; Cundari, E.; Mollica, A.; Coluccia, A.; Naccarato, V.; La Regina, G.; Silvestri, R.; Negri, R. Molecules 2019, 24, e1739
Design, Synthesis and Evaluation. Int J Mol Sci. 2025 Jun 25;26(13):6090
No full textAmong the fundamental pathological processes, tumorigenesis is arguably the most complex. It results from the accumulation of genetic alterations that typically unfold over many years, leading to the gradual breakdown of homeostatic barriers at the cellular, tissue, and ultimately organismal levels. Over the past few decades, discoveries on the molecular and cellular mechanisms of tumorigenesis have had, and continue to have, a profound impact on anticancer pharmacotherapy. It is noteworthy that since the early 2000s, the number of anticancer drugs approved for clinical use has increased from a few dozen [1] to several hundred distinct agents [2]. With the aim of targeting the hallmarks of tumorigenesis [3]—the functional traits that enable cancer cells to survive, proliferate, and disseminate—numerous classes of anticancer drugs are currently under active investigation and development. This Special Issue on “New Anticancer Agents: Design, Synthesis and Evaluation” brings together experimental studies and review articles that, at least in part, reflect the complexity of this disease and highlight several aspects of basic research aimed at therapeutic innovation
Localization of the ribosomal genes in Anguilliformes (Chordata, Osteichthyes)
No full textLocalization of the ribosomal genes in Anguilliformes (Chordata, Osteichthyes)
E. Coluccia, R. Cannas, A. Milia, A. M. Deiana, S. Salvadori
Dipartimento di Biologia Animale ed Ecologia, Università di Cagliari, Viale Poetto 1, 09126 Cagliari, Italy
Keywords: Anguilliformes, FISH, ribosomal genes
Ribosomal genes are organized in two multiple tandemly-arrayed units: the major family encoding for 28S, 18S and 5.8S rRNA and localized in the nucleolar organizer region (NOR), and the minor family encoding for 5S rRNA. Their chromosomal localization represents useful markers for karyotype analysis and for the investigation of the phylogenetic relationships among related species, especially in fishes in which euchromatic structural banding patterns are difficult to obtain.
In the present study, the chromosomal evolution of rDNA within the Anguilliformes order was studied through the mapping by FISH of the two ribosomal gene families in some species from different families, and by comparison with data on other Anguilliformes. 45S rDNA has been mapped in Gymnothorax unicolor (Muraenidae), Conger conger (Congridae), Ophisurus serpens and Echelus myrus (Ophichthidae); it was detected only in a chromosome pair in all species, as in the other previously studied Anguilliformes. This situation is the most frequent in teleosteans. A terminal localization on the short arm of a submetacentric and subtelocentric chromosome pair was found in O. serpens and C. conger respectively; this is the most frequent situation among Anguilliformes and fishes in general; an interstitial location on a acrocentric chromosome pair was detected for G. unicolor and E. myrus. NOR is positive to silver staining and CMA3 banding in all species in which these techniques have been applied. Between the two Mediterranean moray eels (Muraena helena and G. unicolor) a pericentric inversion involved the NOR bearing pair.
The ribosomal gene families are located on separate chromosome pairs in Anguilla anguilla and A. rostrata 1, 2 and in most fishes. In the present study in M. helena, the 5S gene family has been mapped on a pair other than NOR, while in C. conger, both 5S and 45S rDNA were clustered in the same chromosome region.
1 Martínez J.L. et al., Cytogenet Cell Genet, 73, 149.
2 Nieddu M. et al., Genome, 41, 728
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