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Apoptosis Deregulation in Cancer

Department of Experimental Pathology and Oncology
University of Florence - Viale Morgagni 50, 50134 Firenze
Phoenix - ONLUS Stem Cell Foundation for Human Life

Principal Investigator: Prof. Sergio Capaccioli

Experimental Oncology Unit

staff picture  Staff

  • Prof. Sergio Capaccioli, PhD Principal Investigator
    Professor of General Pathology at the Faculties of Medicine and of Pharmacy of the University of Florence
    Group of Research on Apoptosis Molecular Pathology (GRAMP) at the Department of Experimental Pathology and Oncology of the University of Florence, Viale G.B. Morgagni 50, 50100 Firenze
    President of Phoenix ONLUS Stem Cell Foundation for Human Life
    Unit of the Interuniversity Consortium of Biotechnologies (CIB)
    Tel. +39 055 4598208
    Fax +39 055 4598900
    Mobile Phone1 338 5696943
    Mobile Phone2 348 5410896
    sergio@unifi.it
    Web Sites
    www.patgen.eu
    www.stemphoenix.org
    www.cibiotech.it
    www1.unifi.it/plrna
  • Dr. Matteo Lulli, PhD - Researcher fixed-term contract
  • Dr. Ewa Witort, PhD - Research Fellow
  • Dr. Federico Di Gesualdo - Doctorate Student
  • Dr. Rosa Loffredo - Research Fellow
  • Dr. Jacopo Pattarino, MD - Specialist in Plastic Surgery and Doctorate Student
  • Dr. Federico Maria Romano, MD - Specialist in Plastic Surgery and Doctorate Student
  • Dr. Paolo Tenti, MD - Trainee
  • Irene Granucci - Student of Biotechnologies
  • Silvia Bono - Student of Biotechnologies
  • Boaz Palterer - Student of Medicine
  • Matteo Piccini - Student of Medicine
  • Livia Giannini - Student of Medicine

Clinical Partner Unit

Staff

  • Prof. Fabio Cianchi, MD Principal Investigator
    Professor of General Surgery
    Dipartimento di Area Critica Medico Chirurgica
    Sezioni di Anestesiologia e Rianimazione, Clinica Chirurgica Generale e Discipline Chirurgiche, Clinica Chirurgica Generale e Oncologica
    Viale Morgagni, 85 - 50134 Firenze
    Tel. 055 412029 - 4277566
    Fax 055 4220133
    fabio.cianchi@unifi.it
  • Prof. Giuliano Perigli, MD - Professor of General Surgery
  • Dr. Marta Ferraroni, PhD - Researcher
  • Dr. Dimetrio Randazzo, PhD - Technician
  • Dr. Silvia Tilli, PhD - Technician

Chemistry Partner Unit

Staff

  • Prof. Andrea Scozzafava, PhD Principal Investigator
    Professor of Chemistry
    Department of Chemistry
    Bioinorganic Chemistry Laboratory
    Via della Lastruccia 3 - Sesto Fiorentino - 50019 Firenze
    Tel. 055 4573355
    Fax 055 4573333
    andrea.scozzafava@unifi.it
    Web Sites
    www.cibiotech.it
    http://bio.chim.unifi.it
  • Prof. Farizio Briganti, PhD - Professor
  • Dr. Claudiu Supuran, PhD - Researcher
  • Dr. Fabrizio Carta - Research Fellow
  • Dr. Marta Ferraroni, PhD - Researcher
  • Dr. Dimetrio Randazzo, PhD - Technician
  • Dr. Silvia Tilli, PhD - Technician

The Experimental Oncology Unit of Sergio Capaccioli

Research carried out by our Unit is focused on translational studies in molecular oncology. In virtue of our wide national and international collaborations, ranging from chemistry to clinical medicine, and having impact on molecular mechanisms of human diseases, mainly related to apoptotic excesses or defects, the objects of our studies are usually transferred to clinics and very often result in invention patents of pharmacological interest at high impact for human health. Since establishment, our Research Unit has studied the molecular mechanisms that control cellular proliferation during normal and neoplastic growth. In 1994, following a stage of the PI in the lab of Gerard Evan at the Imperial Cancer Research Fund of London, the Unit addressed its research on molecular mechanisms of apoptosis and their deregulation in human pathologies, focusing on degenerative ophthalmologic diseases and cancer.

Focusing on three cancer genes, c-myc, p53 and bcl-2, we have firstly demonstrated that c-myc lowers the cellular apoptotic threshold to genotoxic drugs as well as that of the shift from apoptosis to necrosis via the syncretic process of aponecrosis firstly highlighted in our lab. As to p53, we have demonstrated that cellular lipofection of fragmented DNA as well as of short synthetic DNA segments (oligodeoxyribonucleotides, ODNs) mimics effects of genotoxic agent in that they induce apoptosis via p53 activation. This impacts both on antisense technology and cellular response to cell-free DNA naturally present at high levels in serum of neoplastic patients.

Most important, we were first to demonstrate that bcl-2 expression is also controlled at post-transcriptional level by a mechanism based on interactions between a destabilising AU-Rich Element of its mRNA (ARE) and a number of ARE-binding proteins (AUBPs) that modulates bcl-2 mRNA decay. We have also demonstrated that this mechanism can be disrupted during neoplastic transformation or progression, which accounts for bcl-2 overexpression-related apoptosis defects underlying cancer invasion, metastasis and non specific chemoresistances. The main molecular tools we employ for many years to study gene function and post-transcriptional control of their expression are antisense ODNs or siRNAs able to induce highly specific single gene switch off.

Besides our collaborations with clinicians, the use of antisense ODNs, endowed with evident gene therapeutic potential, contribute to render our research a paradigmatic translational research. The six invention patents we have obtained in these years, with one that has already resulted as a pharmacological drug, strongly support this assertion.

Main Research Themes

Molecular mechanisms of apoptosis: their determinants in normal cells and their alterations in cancer
Main achievement. It has been generally recognized that the role of genetically determined defects of apoptosis play the same pivotal role as proliferation excesses on cancer onset and progression, included invasion, metastasis angiogenesis and chemoresistances. For many years our Unit is involved in studies of cancer genes and in particular apoptosis-related gene alterations, by means of the inverse genetics - that is, the specific inhibition of single gene expression by antisense oligonucleotides (reviewed in 25). Our targeted/studied cancer genes include Ras, MDR1, uPAR, c-Myc, p53, TERT, DHFR, mTor, iNOS, Cox-2, LOS, PTP, NFKB, Bcl-2/IgH, bcl-2. By inhibiting the expression of most of the above genes by antisense strategies, we have added important achievements, described in relevant papers, to the knowledge of their involvement in onset/progression of several types of cancer, from leukemias/lymphomas to colorectal carcinomas. Intriguingly, a number of these genes have resulted to be coregulated at post-transcriptional level.

Current work and Future plans. Studies of the above genes are continuing, essentially in collaboration with three units of this and other universities, lead by: Prof. Enrico Mini (University of Florence), Prof. Fabio Cianchi (University of Florence), Prof. Angelo Nicolin (University of Milan).

Post-transcriptional control of gene expression and its deregulation in cancer: focusing on the main antiapoptotic gene bcl-2.
Main achievement. Cell division, differentiation and apoptosis are modulated by complex genetic programs in which bcl-2 gene often plays a central role. Deregulated bcl-2 expression often occurs in human tumours and plays a key role in cancer growth, metastasis and drug resistance. Genes requiring a fine regulation often possess a peculiar mechanism of expression control acting at post-transcriptional level: complex interactions between adenine and uridine-rich elements (AREs) in the mRNA 3'UTR and ARE-binding proteins (AUBPs) modulate mRNA stability and translation, and thereby, protein level. We firstly described this mechanism for bcl-2 gene, by demonstrating that bcl-2 mRNA half-life is modulated by a conserved ARE (Schiavone et al. 2000), identifying some bcl-2 AUBPs and defining their role in bcl-2 mRNA turnover. These include AUF1 (Lapucci et al. 2002), Bcl-2 itself (Bevilacqua et al 2003b) and a new protein we named Tino/RKHD1 now in the process of further characterisation (Donnini et al. 2004). Furthermore, while the bcl-2 ARE did not present any mutation in the wide variety of human tumours we have analysed, bcl-2 AUBPs revealed a variety of pattern alterations in tumours. This prompted us to focus on the analysis of bcl-2 AUBPs for their putative involvement in cancer onset and/or progression. More recently, integrating RNA affinity chromatography with bidimensional electrophoresis and mass spectrometry analysis, we have identified and characterized ζ-crystallin as a new bcl-2 AUBP involved in bcl-2 over-expression in human acute lymphatic leukemias. To clarify the role of the novel bcl-2 ARE binding protein, ζ-Crystallin (CRYZ), a fine dissection of the molecular pathway underlying the bcl-2 mRNA stability in leukemic T cells was performed. In particular, we used Jurkat T-cells as a paradigm of ALL leukaemias. Here, we have demonstrated that CRYZ, whose levels are higher than in normal T-lymphocytes, is an atypical RNA binding protein endowed with bcl-2 mRNA stabilizing activity, possibly involved in the pathogenesis of acute lymphocytic leukaemia by directly deregulating bcl-2 expression at the post-transcriptional level. Indeed, we have demonstrated that increased levels of BCL-2 protein in Jurkat T cells resulted from CRYZ over-production.

Another additional trans-acting factor involved in the post-transcriptional regulation of bcl-2 gene, disclosed in our lab by means of the RNA Three-hybrid system, is Tino/RKHD1. Tino/RKHD1 is the prototypic member of a family of four genes, hMex-3s, possibly involved in RNA metabolism (Buchet-Poyau K. et al., 2007), as they code RNA-binding proteins possessing KH-modules able to complex with RNAs. The complete family of hMex-3 genes has been recently cloned, however, clear evidences of their biological role are still lacking. A first evidence of their involvement in RNA metabolism comes from Tino/RKHD1 interacting with the bcl-2 ARE motif (Donnini M. et al., 2004). Apparently, Tino/RKHD1 possess an RNA destabilizing activity as it accelerates the decay rate of reporter RNAs containing the bcl-2 ARE (Donnini M. et al., 2004).

To shed light on the functional role of Tino/RKHD1, we exploited its RNA-binding activity to identify additional mRNA transcripts, other than bcl-2 mRNA, directly bound in vivo to this protein. To this goal, a blending of biochemical and computationally-based approaches was applied. The computational analysis was based on FOLDALIGN coupled to Infernal analysis (Eddy S.R. 2006). From the analysis of all RNA sequences within the repertoire of target transcripts, we found a particular common signature: the cis-acting element bound by the RNA-binding protein Quaking (Larocque D. et al. 2005). The concurrent presence of both consensus sequences, of Tino/RKHD1 and Quaking, is certainly reminiscent of the ancient post-transcriptional control based on the orthologous proteins ceMex-3 and GLD-1 in the nematode C. elegans. Here, the two proteins are involved in germ cell development (Mootz D. et al., 2004). They act in spatially different regions in gonads to allow proper oocyte maturation. To this end, ceMex-3 and GLD-1 control common targets in distinct regions. Importantly, ceMex-3 expression is controlled by GLD-1. GLD-1 controlling ceMex-3 represents a rare example of posttranscriptional- switch (Mootz D. et al., 2004). This fact, possibly reflected in mammals on the basis of our disclosure, might be of functional relevance to understand the exact role of Tino/RKHD1.

Finally, another bcl-2 AUBP, the nucleolin, and two microRNAs, mir-15a and mir-16-1, have been demonstrated by others to post-transcriptionally deregulate bcl-2 expression in cancer. Taken together, these emerging results indicate that disruption of the post-transcriptional control of bcl-2 expression, consequent to alterations of its AUBPs and/or binding microRNAs can contribute to the oncogenicity of this antiapoptotic gene.

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Current work and Future plans. The results described above have opened up new exciting perspectives. Consequently, based on the most recent literature and previous personal results, the main tasks of our project are (1) identification and characterization of new regulative bcl-2 AUBPs; (2) identification and characterization of bcl-2 AUBP alterations in human leukemias and solid tumours and assessment of their role in tumour onset/progression; (3) exploring the role of microRNAs in AUBP-dependent control of bcl-2 expression; (4) Finally, based on our long experience in this field, demonstrated by our five patents on molecular tools aimed to modulate bcl-2 expression and to revert the neoplastic phenotype, design the exogenous modulation of ARE-bearing gene expression by new post-transcriptional control targeting tools, as potential gene therapy strategies. Prof. Angelo Nicolin (University of Milan), Prof. Roberto Gherzi (IST, Genova), Prof. Dominique Morellp (University Paul Sabatier, Toulouse, France), Prof. Gary Brewer (University of Robert Wood Johnson Med. School, NJ, USA) are our collaborators in this research.

Post-transcriptional co-regulation of bcl-2 expression with other ARE-bearing cancer genes, focusing on bcl-2, bcl-2/IgH, Bim, HIF-1, CA IX, Cox-2, VEGF, uPA/uPAR, TNFα/TNFr: implication of cancer stem cells.
Main achievement. This is for our Unit a novel research performed with several national and international collaborations, consequent to recent discoveries opening our research perspectives. Based on our previous results and critical and detailed analysis of the literature, which are beyond the scope of this report, we have hypothesized novel intriguing and possibly dangerous liaisons among bcl-2 and other post-transcriptionally regulated ARE bearing genes, playing a key role in cancer onset and progression, being involved in chemoresistance, angiogenesis, invasion and metastasis. Recently, all these cancer phenotypes have been closely related to the molecular response to hypoxia and mediated by the induction of a plethora of cancer-related genes, including VEGF, COX-2, iNOS and uPAR which master switch is HIF-1. Suggestive coregulations of bcl-2 and these genes have been described (Shimizu et al. 2006; Iervolino et al., 2002; Seftel et al., 1999; Trisciuoglio et al. 2004; Trisciuoglio et al. 2005; Cinel L et al., 2002; Anai et al. 2007), most of which are oncogenic relationship (Audic Y et al. 2004: de Silanes I.L. et al., 2007; Steinman R.A, 2007).
On this basis, a thorough understanding of these alterations and their impact on the 3'UTR-directed post-transcriptional gene regulation could uncover new targets for therapeutic intervention, which ascribes an added value to our research.

Current work and Future plans. The main tasks of this research are: 1) unravelling molecular mechanisms underlying interrelations and possible post-transcriptional co-regulations between bcl-2 and other ARE-harbouring genes, which are HIF-1 and some HIF-1 induced genes which are CA IX, COX-2, VEGF and BCL-2. Possible co-regulation with post-transcriptionally regulated inflammatory cytokines will be also evaluated; 2) identification and characterization of alterations of these genes interrelations in cancer, using as experimental models, cultured neoplastic cells, co-cultures of neoplastic cells with inflammatory cells (macrophages), human cancer samples and either mouse models of cancer metastasis or nude mice bearing human cancer cells; 3) evaluating the ability of antisense oligonucleotides to modulate the expression of the above mentioned genes and their potential to be applied pharmacologically as gene therapeutics; 4) evaluating effectiveness of novel CA IX inhibitors in commitment to apoptosis cultured cancer cells in conditions of transient severe hypoxia or selected by severe hypoxia, used as models of cancer stem cells. Prof. Fabio Cianchi (University of Florence), Drs. Gabriella Zupi/Donatella Del Bufalo (Cancer Institute Regina Elena of Roma), Prof. Paola Chiarugi (University of Florence), Proff. Andrea Scozzafava/Claudiu Supuran (University of Florence), Dr. Roberto Gherzi (IST Genova)

Modulation of cancer gene expression by antisense strategies
Main achievement. Efficient and specific modulation of gene expression can be obtained either by producing transgenic or gene knockout organisms and cells (gene targeting), or by treating organisms or cells with short synthetic nucleic acid segments in antisense orientation with respect to the targeted mRNAs and therefore forming heteroduplex RNA/ODN stretches that inhibit mRNA translation to protein (antisense oligonucleotides or aODNs, reviewed in 25). Their target specificity renders aODNs, as well the new siRNAs, optimal tools to study single gene function but also potential post-transcriptional gene therapeutics. Aimed to study cancer gene functions by the inverse genetics, we start this research fifteen years ago with a grant from CNR (PF-ACRO). Have previously analysed uptake, degradation and delivery of ODNs in cultured cells, we have successfully targeted several cancer genes (Ras, MDR1, uPAR, bcl-2/IgH, bcl-2, DHFR, NFKB) with specific cationic lipid-vehiculated aODNs or ribozymes obtaining reversal of the relevant neoplastic phenotype (see our papers and invention patents).

Current work and future plans. Recently, we have patented a new kind of bcl-2 mRNA targeting antisense oligoribonucleotides (ORNs) that stabilize bcl-2 mRNA by complementing with/masking its destabilizing cis-acting ARE and thereby upregulate bcl-2 gene expression, preventing apoptosis (Ghisolfi L et al., 2005; Bevilacqua et al. 2007; Papucci et al. 2008). Based on this observation, targeting destabilizing cis-acting elements of genes regulated at post-transcriptional level could be a quite new and elegant strategy to induce their upregulation in the absence of any gene transfection. In particular, we have designed ARE-targeting synthetic ORNs aimed to exogenously up-regulating HIF-1, COX-2, VEGF, uPAR and CA IX expression (patent in progress) and thereby to study their possible interferences or co-regulations. Prof. Angelo Nicolin (University of Milan) and Dr. Massimo Capobianco (CNR of Bologna)

Melanoma: discovering new molecular diagnostic markers and/or Therapeutic targets
Main achievement. Melanomas are very aggressive and metastatic tumors. The identification of risk factors and early diagnosis are crucial to overcome these cancers and became essential to discover new possible diagnostic markers and/or therapeutic targets. This is for our Unit a novel research project - performed with several national and international collaborations - consequent to recent discoveries opening new research perspectives. The activation of BRAFV600E oncogene, consequent to a mutation occurring in melanomas but also in atypical or dysplastic nevi (Pollock PM et al, 2003; Yazdi AS et al, 2003; Gray-Schopfer V et al, 2007; Hoeflich KP et al. 2009), may be considered a tumor-initiating event. Moreover, a critical role in invasion and metastasis is played by the Tetraspanins, in particular tetraspanin CD63 and TSPAN8, a family of transmembrane proteins involved in tumor progression and metastasis.

Current work and future plans. The main tasks of this research are: 1) analyzing BRAFV600E, tetraspanin CD63 and TSPAN8 expression as well as chromosomal rearrangements in melanomas as diagnostic markers and/or therapeutic targets; 2) analyzing microRNA expression profiles as markers of neoplastic progression. This project will be performed by the Phoenix Stem Cell Foundation for Human Life research group in collaboration with Prof. Nicola Pimpinelli coordinated interfaculty team.

Publications

Research Articles and Reviews last five years

  1. Schiavone N., Donnini M., Nicolin A., Capaccioli S. Antisense oligonucleotide drug design. Current Pharmaceutical Design 10, 769-784, 2004
  2. Papucci L., Formigli L., Schiavone N., Tani A., Donnini M., Lapucci A., Perna F., Tempestini A., Witort E., Nosi D., Orlandini E.G., Zecchi Orlandini S. and Capaccioli S. Apoptosis shifts to necrosis via intermediate types of cell death by a mechanism depending on c-myc and bcl-2 expression in Antimycin A-treated cells Cell Tissue Res. 316:197–209, 2004
  3. Chiarugi P., Taddei M.L., Schiavone N., Papucci L., Giannoni E. , Capaccioli S., Raugei G. and Ramponi G.P. LMW-PTP is a positive regulator of tumor onset and growth. Oncogene 23:3905-3914, 2004
  4. Donnini M., Lapucci A., Papucci L.., Witort E., Jacquier A., Brewer, G., Nicolin A., Capaccioli S. and Schiavone N. Identification of Tino: a new evolutionarily conserved bcl-2 AU-rich element RNA binding protein J. Biol. Chem. 279:20154-20166, 2004
  5. Granchi D., Amato I., Battistelli L., Avnet S., Capaccioli S., Papucci L., Donnini M., Brandi M.L., Giunti A. and Baldini N. In vitro blockade of receptor activator of nuclear factor-kappaB ligand prevents osteoclastogenesis induced by neuroblastoma cells. Int. J. Cancer 111:829-838, 2004
  6. Asnaghi L, Calastretti A, Bevilacqua A, D'Agnano I, Gatti G, Canti G, Delia D, Capaccioli S, Nicolin A. Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene. 23:5781-5791, 2004
  7. Witort E.J., Dini M., Pattarino J., Papucci L., Schiavone N., Donnini M., Lapucci A., Lo Russo G., Lo Russo D. and Capaccioli S. Coenzyme Q10 prevents adipocyte apoptosis following collection for lipofilling. Clinical and Experimental Plastic Surgery 36:67-70, 2004
  8. Ghisolfi L., Papucci L., Bevilacqua A., Canti G., Tataranni G., Lapucci A., Schiavone N., Capaccioli S., Nicolin A. Increased Bcl2 expression by antisense oligoribonucleotides targeting the ARE motif. Molecular Pharmacology 68:816-821, 2005
  9. Cianchi F., Cortesini C, Schiavone N, Perna F, Magnelli L, Fanti E, Bani D, Messerini L, Fabbroni V, Perigli G, Capaccioli S., Masini E. The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clin Cancer Res. 11:6807-6815, 2005
  10. Tempestini A., Caciagli B., Morganti M., Witort E., Nobili S., Papucci L., Schiavone N., Donnini M., Landini I., Lapucci A., Perna F., Lulli M., Mazzei T., Sobrero A., Mini E., Capaccioli S. Molecular characterization of established human colon carcinoma cell lines (HCT-8) made resistant to 5-fluorouracil by different selection schedules. Oncology Res. 16:143-156, 2005
  11. Cianchi F, Cortesini C, Magnelli L, Fanti E, Papucci L, Schiavone N, Messerini L, Vannacci A, Capaccioli S, Perna F, Lulli M, Fabbroni V, Perigli G, Bechi P, Masini E. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells. Mol Cancer Ther. 5:2716-26, 2006
  12. Bevilacqua A., Ghisolfi L., Franzi S., Maresca G., Gherzi R., Capaccioli S., Nicolin A., Canti G. Stabilization of cellular mRNAs and upregulation of proteins by oligoribonucleotides homologous to the Bcl2 ARE motif. Mol Pharmacol. 71:531-538, 2007
  13. Witort E.J., Pattarino J., Papucci L., Schiavone N., Donnini M., Lapucci A., Lulli M., Lo Russo G., Mori A., Dini M., Capaccioli S. Autologous lipofilling: Coenzyme Q10 can rescue adipocytes from stress-induced apoptotic death. Plastic and Reconstructive Surgery 119:1191-1199, 2007.
  14. Papucci L., Witort E., Bevilacqua A.M., Donnini M., Lulli M., Borchi, E. Khabar K.S.A., Tempestini A., Lapucci A., Schiavone N., Nicolin A. and Capaccioli S. Impact of targeting the AU-rich element of bcl-2 mRNA with oligoribonucleotides on apoptosis, cell cycle and neuronal differentiation in SHSY-5Y cells. Mol Pharmacol. 73:498-508, 2008
  15. Cianchi F, Papucci L., Schiavone N., Lulli, Magnelli L., Vinci M.C., Messerini L., Manera C., Ronconi E., Romagnani P., Donnini M., Perigli G., Trallori G., Tanganelli E, Capaccioli S. and Masini E. Cannabinoid receptor activation induces apoptosis through tumor necrosis factor α-mediated ceramide de novo synthesis in colon cancer cells. Clinical Cancer Research 14:7691-7700 2008
  16. Papucci L., Witort E., Schiavone N., Donnini M., Lapucci A., Lulli M., Lazzarano S., Simoncini M., Mazzoni T., Falciani P.G. and Capaccioli S. Topical administration of the mitochondrial PTP opening inhibitor COQ10 prevents apoptotic cell death induced by UVC-irradiation in rat corneas and rabbit retinas. Journal of Gravitational Physiology 2008.
  17. Lulli M., Papucci L., Witort E., Donnini M., Lapucci A., Lazzarano S., Mazzoni T., Simoncini M., Falciani P. and Capaccioli S. Proposed Pharmacological countermeasures against apoptotic cell death in experimental models mimicking space environment damage. Journal of Gravitational Physiology 2008.
  18. Lazzarano S., Lulli M., Fibbi G., Margheri F., Papucci L., Serrati S., Witort E., Chillà A., Lapucci A., Donnini M., Quaglierini P., Romiti A., Specogna R., Del Rosso M and Capaccioli S. Anti-urokinase receptor antisense oligonucleotide (UPAR-aODN) to prevent and cure long-term space explorations-related retinal pathologic angiogenesis. Journal of Gravitational Physiology 2008.
  19. Nobili S., Lippi D., Witort E., Donnini M., Bausi L., Mini E. and Capaccioli S. Natural compounds for cancer treatment and prevention Pharmacological Research, 59:365-378, 2009
  20. Autelli R., Ullio C., Prigione E., Crepaldi S., Schiavone N.,Brunk U.T., Capaccioli S., Baccino F.M. and Bonelli G. Divergent pathways for TNF and C2-ceramide toxicity in HTC hepatoma cells. Biochimica et Biophysica Acta 1793:1182-1190, 2009
  21. Ghisolfi L., Calastretti A., Franzi S., Canti G., Donnini M, Capaccioli S., Nicolin A., Bevilacqua A. B Cell Lymphoma (BCL)-2 protein is the major determinant in Bcl-2 Adenine-uridine Rich-Element turnover overcoming Hur activity. Journal of Biological Chemistry, 284:20946-20955, 2009
  22. Lapucci A., Lulli M., Amedei A., Papucci L., Witort E., Di Gesualdo F., Bertolini F., Brewer G., Nicolin A., Schiavone N., Morello D., Donnini M., Capaccioli S. ζ-Crystallin is a bcl-2 mRNA binding protein involved in bcl-2 over-expression in T-cell Acute Lymphocytic Leukemia FASEB J. 2010, in press
  23. Lulli M., Di Gesualdo F. Witort E., Pessina A., Capaccioli S., Cell Death: Physiopathological and Therapeutic Implications - Annual Meeting of the Associazione Italiana di Colture Cellulari (ONLUS-AICC: Italian branch of the European Tissue Culture Society) in collaboration with Phoenix-ONLUS Stem Cell Foundation for Human Life, 2-4 December 2009, Florence (Italy. Cell Death & Disease 2010, in press

Scientific Books
Sergio Capaccioli is responsible of the Italian version of "Recombinant DNA" by J. Watson (Zanichelli ed.)

Invention Patents

  1. Capaccioli S., Del Rosso M., Fibbi G. and Quattrone A. Antimessenger oligonucleotide against urokinase receptor. US Patent 5872106 Issued on February 16, 1999
  2. Capaccioli S., Morelli S. and Nicolin A. Antisense transcript associated to tumor cells having a T(14;18) translocation and oligodeoxynucleotides useful in the diagnosis and treatment of said tumor cells. US Patent 6005095 Issued on December 21, 1999
  3. Capaccioli S., Cutrì M., Quattrone A. e Schiavone N. Ciclizzatore termico per reazioni biotecnologiche in particolare per poylmerase chain reaction e relativo contenitore per reazioni. Brevetto ITMI981683, 21/01/2000
  4. Brancato R., Capaccioli S., Donnini M. Lapucci A. Papucci L., Schiavone N., Tempestini A. "Oligonucleotidi antisenso che regolano l'espressione del gene anti-apoptotico bcl-2". Brevetto No 6623 M, Novembre 9, 2001.
  5. Brancato R., Capaccioli S., Saettone M.F., Schiavone N. Use of ubiquinone Q10 for the local treatment and prevention of post-surgical ophthalmologic pathologies. US Patent 6787572 Issued on September 7, 2004
  6. Capaccioli S., Dini M., Donnini M. Lapucci A., Lo Russo D., Papucci L., Pattarino J., Schiavone N., Witort E. Coenzyme Q10 as antiapoptotic agent. European Publication Number US200612738 on 15/06/2006
  7. Brancato R., Capaccioli S., Lenaz G., Schiavone N. Use of quinone Q10 for the treatment of ocular diseases. US Patent 7029672 Issued on April 18, 2006

Collaborations

  • Prof. Gary Brewer - Department of Molecular Genetics and Microbiology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, 08854, Piscataway, NJ, USA
  • Prof. Dominique Morello - Centre de Biologie du Développement, CNRS-UMR 5547, IFR 109, Université Paul Sabatier, Bâtiment 4R3, 118 Route de Narbonne, 31062 Toulouse Cedex 4, France
  • Dr. Monica Monici - ASAcampus, ASA srl, o Dip. Fisiopatologia Clinica, Università di Firenze
  • Dr. Massimo Dal Monte - Dipartimento di Biologia, Università di Pisa, Pisa (Italy)
  • Dr. Lucia Morbidelli - Dipartimento di Biologia Molecolare, Universita' degli Studi di Siena, Siena (Italy)
  • Dr. Marc Billaud - CNRS Unité Mixte de Recherche 5201, Laboratoire de Génétique Moléculaire, Signalisation et Cancer, F-69008 Lyon, France
  • Prof. Alain Jaquier - Unité de Génétique des Interactions Macromoléculaires. Institut Pasteur, 25 Rue du Dr. Roux, Paris, France
  • Prof. Angelo Nicolin - Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy
  • Dr.ssa Gabriella Zupi and Donatella Del Bufalo - Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy
  • Dr. Roberto Gherzi - Istituto Nazionale per la Ricerca sul Cancro (IST) di Genova, Genova, Italy
  • Prof. Stefano Cacchione - Dipartimento di Genetica e Biologia Molecolare, Università di Roma La Sapienza, Roma, Italy
  • Dr. Massimo Capobianco - Istituto di Sintesi Organica e Fotoreattività del Consiglio Nazionale delle Ricerche, Via Gobetti 101, 40129 Bologna, Italy
  • Dr. Giuseppina De Simone - Istituto di Biostrutture e Bioimmagini-CNR, Napoli, Italy
  • Prof. Andrea Scozzafava and Claudiu Supuran - Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Dipartimento di Chimica, Università degli Studi di Firenze, Sesto Fiorentino, Firenze, Italy
  • Prof. Rosario Brancato - Director of the School of Ophthalmology, University Hospital San Raffaele, Via Olgettina 60, Milan 20132, Italy
  • Prof. Carlo Nucci - Cattedra di Ottica Fisiopatologia, Dipartimento di Biopatologia e Diagnostica per Immagini, Università di Roma Tor Vergata, Rome, Italy
  • Prof. Enrico Mini - Dipartimento di Farmacologia Preclinica e Clinica. Università di Firenze, Università degli Studi di Firenze, Firenze
  • Prof. Sandra Zecchi - Dipartimento di Anatomia, Istologia e Medicina Legale - Università di Firenze, Firenze

The Clinical Partner Unit of Fabio Cianchi

In the last 10 years, his scientific interest has been directed toward the study of the molecular and genetic mechanisms involved in colorectal carcinogenesis with the aim to find new molecular-target therapies. He is the author and co-author of more than 200 scientific papers and communications, the majority of whom have been published on international scientific journals with high impact factors. He also acts as referee for several international scientific journals in the field of surgical oncology. His clinical activity mainly concerns the surgical oncology of the alimentary tract and the surgical treatment of the esophageal functional disorders with laparoscopic approach.

Publications

  1. Cianchi F., Messerini L, Comin Ce, Boddi V, Perna F, Perigli G, Cortesini C. (2007). Pathologic determinants of survival after resection of T3N0 (Stage IIA) colorectal cancer: proposal for a new prognostic model. Diseases Of The Colon & Rectum. vol. 50, pp.1332-1341 ISSN: 0012-3706.
  2. Perigli G, Cortesini C, Qirici E, Boni D, Cianchi F. (2007). Clinical benefits of minimally invasive techniques in thyroid surgery. World Journal Of Surgery. ISSN: 0364-2313.
  3. Cianchi F., C. Cortesini, F. Perna, V. Fabbroni, C. Uliva, F. Fabrizi, L. Giannini, A. Vannacci, E. Masini. (2006). Prostaglandin E2 correlates with histamine production in human colorectal cancer. Inflammation Research. vol. 55, pp. S81-S82 ISSN:1023-3830.
  4. Cianchi F., Cortesini C, Magnelli L, Fanti E, Papucci L, Schiavone N, Messerini L, Vannacci A, Capaccioli S, Perna F, Lulli M, Fabbroni V, Perigli G, Bechi P, Masini E. (2006). Inhibition of 5-lipoxygenase by MK886 augments the antitumor activityof celecoxib in human colon cancer cells. Molecular Cancer Therapeutics. vol. 5, pp. 2716-2726 ISSN: 1535-7163.
  5. Gelmini S, Poggesi M, Pinzani P, Mannurita Sc, Cianchi F., Valanzano R, Orlando C. (2006). Distribution of Tankyrase-1mRNA expression in colon cancer and its prospective correlation with progression stage. Oncology Reports. vol. 16, pp. 1261-1266 ISSN:1021-335X.
  6. L. Messerini, Cianchi F., C. Cortesini, C. Comin. (2006). Incidence and prognostic significance of occult tumor cells in lymph nodesfrom patients with stage IIA colorectal carcinoma. Human Pathology. vol. 37, pp. 1259-1267 ISSN: 0046-8177.
  7. Mazzanti R, Solazzo M, Fantappie O, Elfering S, Pantaleo P, Bechi P, Cianchi F., Ettl A, Giulivi C. (2006). Differential expression proteomics of human colon cancer. American Journal Of Physiology. vol. 26 ISSN: 0002-9513. Pubblicazione attualmente solo in linea.
  8. Cianchi F., Cortesini C, Schiavone N, Perna F, Magnelli L, Fanti E, Bani D, Messerini L, Fabbroni V, Perigli G, Capaccioli S, Masini E. (2005). The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clinical Cancer Research. vol. 11, pp. 6807-6815 ISSN: 1078-0432.
  9. Morganti M, Ciantelli M, Giglioni B, Putignano Al, Nobili S, Papi L, Landini I, Napoli C, Valanzano R, Cianchi F.,Boddi V, Tonelli F, Cortesini C, Mazzei T, Genuardi M, Mini E. (2005). Relationships between promoter polymorphisms in thethymidylate synthase gene and mRNA levels in colorectal cancers. European Journal Of Cancer. vol. 41, pp. 2176-2183 ISSN:0959-8049.
  10. Raggi Cc, Cianchi F., Valanzano R, Smith Mc, Serio M, Maggi M, Orlando C. (2005). Prognostic value of somatostatin receptor subtype 2 expression in colorectal cancer. Regulatory Peptides. vol. 132, pp. 23-26 ISSN: 0167-0115.
  11. Cianchi F., Cortesini C, Fantappie O, Messerini L, Sardi I, Lasagna N, Perna F, Fabbroni V, Di Felice A, Perigli G, Mazzanti R, Masini E. (2004). Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer. Clinical Cancer Research. vol. 10, pp. 2694-2704 ISSN: 1078-0432.
  12. Cianchi F., Cortesini C, Fantappie O, Messerini L, Schiavone N, Vannacci A, Nistri S, Sardi I, Baroni G, Marzocca C, Perna F, Mazzanti R, Bechi P, Masini E. (2003). Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis. American Journal Of Pathology. vol. 162, pp. 793-801 ISSN: 0002-9440.
  13. Casini Raggi C, Calabro A, Renzi D, Briganti V, Cianchi F., Messerini L, Valanzano R, Cameron Smith M, Cortesini C, Tonelli F, Serio M, Maggi M, Orlando C. (2002). Quantitative evaluation of somatostatin receptor subtype 2 expression in sporadic colorectal tumor and in the corresponding normal mucosa. Clinical Cancer Research. vol. 8, pp. 419-427 ISSN: 1078-0432.
  14. Cianchi F., Palomba A, Boddi V, Messerini L, Pucciani F, Perigli G, Bechi P, Cortesini C. (2002). Lymph node recovery from colorectal tumor specimens: recommendation for a minimum number of lymph nodes to be examined. World Journal Of Surgery. vol. 26, pp. 384-389 ISSN: 0364-2313.
  15. Cianchi F., Palomba A, Messerini L, Boddi V, Asirelli G, Perigli G, Bechi P, Taddei A, Pucciani F, Cortesini C. (2002). Tumor angiogenesis in lymph node-negative rectal cancer: correlation with clinicopathological parameters and prognosis. Annals Of Surgical Oncology. vol. 9, pp. 20-26 ISSN: 1068-9265.
  16. De Filippo C, Luceri C, Caderni G, Pacini M, Messerini L, Biggeri A, Mini E, Tonelli F, Cianchi F., Dolara P. (2002). Mutations of the APC gene in human sporadic colorectal cancers. Scandinavian Journal Of Gastroenterology. vol. 37, pp.1048-1053 ISSN: 0036-5521.
  17. Luceri C, De Filippo C, Guglielmi F, Caderni G, Messerini L, Biggeri A, Mini E, Tonelli F, Cianchi F., Dolara P. (2002). Microsatellite instability in a population of sporadic colorectal cancers: correlation between genetic and pathological profiles. Digestive And Liver Disease. vol. 34, pp. 553-559 ISSN: 1590-8658.
  18. Cianchi F., Cortesini C, Bechi P, Fantappie O, Messerini L, Vannacci A, Sardi I, Baroni G, Boddi V, Mazzanti R, Masini E. (2001). Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology. vol. 121, pp. 1339-1347 ISSN: 0892-1601.
  19. D'elios Mm, Bergman Mp, Azzurri A, Amedei A, Benagiano M, De Pont Jj, Cianchi F., Vandenbroucke-Grauls Cm, Romagnani S, Appelmelk Bj, Del Prete G. (2001). H(+),K(+)-atpase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology. vol. 120, pp. 377-386 ISSN: 0892-1601.

The Chemistry Partner Unit of Andrea Scozzafava with Claudiu Supuran

The research unit of Andrea Scozzafava is involved in the structure-function characterization of metalloenzymes. In particular two distinct research lines are active which are related to metalloenzymes involved in biodegradative processes or in human diseases. With reference to the first topic new ring opening dioxygenases and mushroom laccases have been characterized. Regarding the biomedical area, the studied enzymes have been in particular carbonic anhydrase and some metalloproteases. The research unit, beside expressing and isolating new enzymes is also capable to determine their three-dimensional structure through X ray diffraction studies, as well as of synthesizing new molecules which can act as inhibitors or activators of the enzymes.

Very many papers have been published regarding the synthesis and characterization of these inhibitors/activators and the structures of the enzyme/inhibitor(activator) adducts. In many cases the new molecules have properties such to be used as potential drugs. In particular carbonic anhydrase inhibitors can be used for the treatment of glaucoma, obesity and for diagnostic purposes at the very early stage of development of malignant tumors i.e. Kidney tumors.

In the case of industrial application of degradative enzymes new approaches have been developed though the use of micellar systems which enhance the activity of native or engineerized microorganisms toward hydrophobic substrates. In this manner it is possible for example to accelerate the degradation of the substrate (bioremediation purposes) or to obtain intermediates with high added value from the substrates (an example of "green chemistry" through an enzymatic approach). The research unit has fruitful scientific collaborations with many excellent European and non European research institutions.

Publications

Research Articles

  1. Cecchi A, Ciani L, Winum JY, Montero JL, Scozzafava A, Ristori S, Supuran CT. Carbonic anhydrase inhibitors: design of spin-labeled sulfonamides incorporating TEMPO moieties as probes for cytosolic or transmembrane isozymes. Bioorg Med Chem Lett. 2008 Jun 15;18(12):3475-80.
  2. Innocenti A, Hilvo M, Scozzafava A, Parkkila S, Supuran CT. Carbonic anhydrase inhibitors: Inhibition of the new membrane-associated isoform XV with phenols. Bioorg Med Chem Lett. 2008 Jun 15;18(12):3593-6.
  3. D'Ambrosio K, Vitale RM, Dogne´ JM, Masereel B, Innocenti A, Scozzafava A, De Simone G, Supuran CT. Carbonic Anhydrase Inhibitors: Bioreductive Nitro-Containing Sulfonamides with Selectivity for Targeting the Tumor Associated Isoforms IX and XII. J Med Chem. 2008 Jun 12;51(11):3230-3237.
  4. Ilies MA, Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors. Part 91. Metal complexes of heterocyclic sulfonamides as potential pharmacological agents in the treatment of gastric Acid secretion imbalances. Met Based Drugs. 2000;7(2):57-62.
  5. Gullotto A, Branciamore S, Duchi I, Caño MF, Randazzo D, Tilli S, Giardina P, Sannia G, Scozzafava A, Briganti F. Combined action of a bacterial monooxygenase and a fungal laccase for the biodegradation of mono- and poly-aromatic hydrocarbons. Bioresour Technol. 2008 Apr 11. [Epub ahead of print]
  6. Thiry A, Rolin S, Vullo D, Frankart A, Scozzafava A, Dogné JM, Wouters J, Supuran CT, Masereel B. Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents: Structure-activity relationship and pharmacological evaluation. Eur J Med Chem. 2008 Feb 29. [Epub ahead of print]
  7. Temperini C, Cecchi A, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors. Interaction of indapamide and related diuretics with 12 mammalian isozymes and X-ray crystallographic studies for the indapamide-isozyme II adduct. Bioorg Med Chem Lett. 2008 Apr 15;18(8):2567-73. Epub 2008 Mar 20.
  8. Randazzo D, Ferraroni M, Scozzafava A, Golovleva L, Briganti F. Biotransformation of chloroaromatics: the impact of bioavailability and substrate specificity. Bioinorg Chem Appl. 2004:209-23.
  9. Di Fiore A, Pedone C, Antel J, Waldeck H, Witte A, Wurl M, Scozzafava A, Supuran CT, De Simone G. Carbonic anhydrase inhibitors: the X-ray crystal structure of ethoxzolamide complexed to human isoform II reveals the importance of thr200 and gln92 for obtaining tight-binding inhibitors. Bioorg Med Chem Lett. 2008 Apr 15;18(8):2669-74. Epub 2008 Mar 18.
  10. Innocenti A, Scozzafava A, Parkkila S, Puccetti L, De Simone G, Supuran CT. Investigations of the esterase, phosphatase, and sulfatase activities of the cytosolic mammalian carbonic anhydrase isoforms I, II, and XIII with 4-nitrophenyl esters as substrates. Bioorg Med Chem Lett. 2008 Apr 1;18(7):2267-71. Epub 2008 Mar 7.
  11. Almajan GL, Barbuceanu SF, Innocenti A, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors. Inhibition of the cytosolic and tumor-associated carbonic anhydrase isozymes I, II and IX with some 1,3,4-oxadiazole- and 1,2,4-triazole-thiols. J Enzyme Inhib Med Chem. 2008 Feb;23(1):101-7.
  12. Temperini C, Scozzafava A, Supuran CT. Carbonic anhydrase activation and the drug design. Curr Pharm Des. 2008;14(7):708-15. Review.
  13. Mincione F, Scozzafava A, Supuran CT.The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. Curr Pharm Des. 2008;14(7):649-54. Review.
  14. Winum JY, Scozzafava A, Montero JL, Supuran CT. Design of zinc binding functions for carbonic anhydrase inhibitors. Curr Pharm Des. 2008;14(7):615-21. Review.
  15. Innocenti A, Hilvo M, Scozzafava A, Lindfors M, Nordlund HR, Kulomaa MS, Parkkila S, Supuran CT. Carbonic anhydrase inhibitors: the very weak inhibitors dithiothreitol, beta-mercaptoethanol, tris(carboxyethyl)phosphine and threitol interfere with the binding of sulfonamides to isozymes II and IX. Bioorg Med Chem Lett. 2008 Mar 15;18(6):1898-903. Epub 2008 Feb 9.
  16. Pastorekova S, Vullo D, Nishimori I, Scozzafava A, Pastorek J, Supuran CT. Carbonic anhydrase activators: activation of the human tumor-associated isozymes IX and XII with amino acids and amines. Bioorg Med Chem. 2008 Apr 1;16(7):3530-6. Epub 2008 Feb 13.
  17. Ciullini I, Tilli S, Scozzafava A, Briganti F. Fungal laccase, cellobiose dehydrogenase, and chemical mediators: Combined actions for the decolorization of different classes of textile dyes. Bioresour Technol. 2008 Oct;99(15):7003-10. Epub 2008 Feb 20.
  18. Saczewski F, Innocenti A, Slawinski J, Kornicka A, Brzozowski Z, Pomarnacka E, Scozzafava A, Temperini C, Supuran CT. Carbonic anhydrase inhibitors: inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides. Bioorg Med Chem. 2008 Apr 1;16(7):3933-40. Epub 2008 Jan 26.
  19. Innocenti A, Vullo D, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors: interactions of phenols with the 12 catalytically active mammalian isoforms (CA I-XIV). Bioorg Med Chem Lett. 2008 Mar 1;18(5):1583-7. Epub 2008 Jan 26.
  20. Temperini C, Cecchi A, Boyle NA, Scozzafava A, Cabeza JE, Wentworth P Jr, Blackburn GM, Supuran CT. Carbonic anhydrase inhibitors. Interaction of 2-N,N-dimethylamino-1,3,4-thiadiazole-5-methanesulfonamide with 12 mammalian isoforms: kinetic and X-ray crystallographic studies. Bioorg Med Chem Lett. 2008 Feb 1;18(3):999-1005. Epub 2007 Dec 15.
  21. D'Ambrosio K, Masereel B, Thiry A, Scozzafava A, Supuran CT, De Simone G. Carbonic anhydrase inhibitors: binding of indanesulfonamides to the human isoform II. ChemMedChem. 2008 Mar;3(3):473-7.

Fifteen Reviews of Claudiu Supuran

  1. Supuran CT. Development of small molecule carbonic anhydrase IX inhibitors. BJU Int. 2008 Jun;101 Suppl 4:39-40. Review.
  2. Temperini C, Scozzafava A, Supuran CT. Carbonic anhydrase activation and the drug design. Curr Pharm Des. 2008;14(7):708-15. Review.
  3. Cecchi A, Supuran CT. Fluorescence- and spin-labeled carbonic anhydrase inhibitors. Curr Pharm Des. 2008;14(7):699-707. Review.
  4. Dogné JM, Thiry A, Supuran CT. Carbonic anhydrase inhibition: insight into non-COX-2 pharmacological effect of some coxibs. Curr Pharm Des. 2008;14(7):679-84.
  5. Hilvo M, Innocenti A, Monti SM, De Simone G, Supuran CT, Parkkila S. Recent advances in research on the most novel carbonic anhydrases, CA XIII and XV. Curr Pharm Des. 2008;14(7):672-8. Review.
  6. Thiry A, Dogné JM, Supuran CT, Masereel B. Anticonvulsant sulfonamides /sulfamates /sulfamides with carbonic anhydrase inhibitory activity: drug design and mechanism of action. Curr Pharm Des. 2008;14(7):661-71. Review.
  7. De Simone G, Di Fiore A, Supuran CT. Are carbonic anhydrase inhibitors suitable for obtaining antiobesity drugs? Curr Pharm Des. 2008;14(7):655-60. Review.
  8. Mincione F, Scozzafava A, Supuran CT. The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. Curr Pharm Des. 2008;14(7):649-54. Review.
  9. Supuran CT. Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. Curr Pharm Des. 2008;14(7):641-8. Review.
  10. Krungkrai J, Supuran CT. The alpha-carbonic anhydrase from the malaria parasite and its inhibition. Curr Pharm Des. 2008;14(7):631-40. Review.
  11. Nishimori I, Onishi S, Takeuchi H, Supuran CT. The alpha and beta classes carbonic anhydrases from Helicobacter pylori as novel drug targets. Curr Pharm Des. 2008;14(7):622-30. Review.
  12. Winum JY, Scozzafava A, Montero JL, Supuran CT. Design of zinc binding functions for carbonic anhydrase inhibitors. Curr Pharm Des. 2008;14(7):615-21. Review.
  13. Supuran CT. Carbonic anhydrases: an overview. Curr Pharm Des. 2008;14(7):603-14. Review.
  14. Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008 Feb;7(2):168-81. Review.

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