Cancer therapy group

Av. Diagonal 643, 08028 Barcelona

Phone. (93) 403-4455, Fax: (93) 402-4520, E-mail : CCiudad@ub.edu

OBJECTIVES

To improve already existent cancer chemotherapy treatments to increase their effectivity.
To investigate new alternative therapies based on the new developments in Biochemistry and Molecular Biology.

As a model we use the gene encoding for Dihydrofolate reductase (DHFR), enzyme that it is widely used as the target for the chemotherapy that uses methotrexate.

RESEARCH INTERESTS

To study the process that develops resistance to chemotherapy.
To find modulators of chemotherapy resistance
To study the transcriptional regulation of the dhfr gene
To study the effect of transcription factors, oncogenes and tumor suppressors on the expression of the dhfr gene.
To investigate in detail the regulation of the transcription factor Sp1 and Sp3
To explore the postranscriptional regulation of the DHFR RNA.
To investigate the role of introns on the expression of the dhfr gene into protein
Cloning of genes responsible for the resistance that arises upon cancer chemotherapy.
Probing the applicability of antisense oligonucleotides and siRNA in cancer therapy
To generate and isolate aptamers for DHFR protein with the aim to inhibit this enzyme.
To design liposomes and immunoliposomes for introducing oligonucleotides into the cells.
Identification of target genes involved in the activation of apoptosis and in the inhibition of angiogenesis: Survivin.
To study the effect of TFOs (Triplex forming oligonucleotides) on dhfr transcription
To repair DNA mutations within the endogenous locus using TFBOs (Triplex Forming Bifunctional Oligonucleotides) and Hairpins. Usage of polipurine hairpins against gene expression
Genomic studies related to Methotrexate resistance: Arrays and MicroArrays
Regulation of Methotrexate resistance by microRNAs
Networking of differentially expressed genes in methotrexate resistant cells

RESEARCH TEAM

Carlos J Ciudad Full Professor

Verònica Noé Researcher

Alicia Tapias Ph.D. Fellow

Elisabet Selga Ph.D. Fellow

Cristina Almagro Ph.D. Fellow

SCIENTIFIC PUBLICATIONS

Transcriptional regulation of the 5'-flanking region of the human transcription factor Sp3 gene by NF-1, c-Myb, B-Myb, AP-1 and E2F. Tapias A, Ciudad CJ, Noé V. Biochim Biophys Acta. 2008 May;1779(5):318-29. <><><>

Transcriptional regulation of aldo-keto reductase 1C1 in HT29 human colon cancer cells resistant to methotrexate: role in the cell cycle and apoptosis. Selga E, Noé V, Ciudad CJ.

Biochem Pharmacol. 2008 Jan 15;75(2):414-26. Epub 2007 Sep 8.
Short-term oleoyl-estrone treatment affects capacity to manage lipids in rat adipose tissue.

Salas A, Noé V, Ciudad CJ, Romero MM, Remesar X, Esteve M.

BMC Genomics. 2007 Aug 28;8:292.
Complexes of Pd(II) and Pt(II) with 9-Aminoacridine: Reactions with DNA and Study of Their Antiproliferative Activity. Riera X, Moreno V, Ciudad CJ, Noe V, Font-Bardía M, Solans X. Bioinorg Chem Appl. 2007:98732.

Differentially expressed genes between high-risk human papillomavirus types in human cervical cancer cells.Vazquez-Ortiz G, García JA, Ciudad CJ, Noé V, Peñuelas S, López-Romero R, Mendoza-Lorenzo P, Piña-Sánchez P, Salcedo M.

Int J Gynecol Cancer. 2007 Mar-Apr;17(2):484-91. Epub 2007 Feb 14.
Pentose phosphate cycle oxidative and nonoxidative balance: A new vulnerable target for overcoming drug resistance in cancer. Ramos-Montoya A, Lee WN, Bassilian S, Lim S, Trebukhina RV, Kazhyna MV, Ciudad CJ, Noé V, Centelles JJ, Cascante M. Int J Cancer. 2006 Dec 15;119(12):2733-41.

Strand displacement of double-stranded DNA by triplex-forming antiparallel purine-hairpins. Coma S, Noe V, Eritja R, Ciudad CJ. Oligonucleotides. 2005 Dec;15(4):269-83.

Gene identification by cDNA arrays in HPV-positive cervical cancer. Vazquez-Ortiz G, Ciudad CJ, Pina P, Vazquez K, Hidalgo A, Alatorre B, Garcia JA, Salamanca F, Peralta-Rodriguez R, Rangel A, Salcedo M. Arch Med Res. 2005 Sep-Oct;36(5):448-58

Characterization of the 5'-flanking region of the human transcription factor Sp3 gene. Tapias A, Monasterio P, Ciudad CJ, Noe V. Biochim Biophys Acta. 2005 Aug 15;1730(2):126-36.

Anti-migratory and anti-angiogenic effect of p16: a novel localization at membrane ruffles and lamellipodia in endothelial cells. Alhaja E, Adan J, Pagan R, Mitjans F, Cascallo M, Rodriguez M, Noe V, Ciudad CJ, Mazo A, Vilaro S, Piulats J. Angiogenesis. 2004;7(4):323-33.

Modulation of IMPDH2, survivin, topoisomerase I and vimentin increases sensitivity to methotrexate in HT29 human colon cancer cells. Penuelas S, Noe V, Ciudad CJ. FEBS J. 2005 Feb;272(3):696-710.

Targeting of sterically stabilised pH-sensitive liposomes to human T-leukaemia cells. Fonseca C, Moreira JN, Ciudad CJ, Pedroso de Lima MC, Simoes S. Eur J Pharm Biopharm. 2005 Feb;59(2):359-66.

Sensitization of human erythroleukemia K562 cells resistant to methotrexate by inhibiting IMPDH. Penuelas S, Noe V, Morales R, Ciudad CJ. Med Sci Monit. 2005 Jan;11(1):BR6-12.

A highly efficient electroporation method for the transfection of endothelial cells. Hernandez JL, Coll T, Ciudad CJ. Angiogenesis. 2004;7(3):235-41.

Expression profiles of a human pancreatic cancer cell line upon induction of apoptosis: Search for modulators in cancer therapy. Blasco F, Penuelas S, Cascallo M, Hernandez JL, Alemany C, Masa M, Calbo J, Soler M, Nicolas M, Perez-Torras S, Gomez A, Tarrason G, Noe V, Mazo A, Ciudad CJ, Piulats J. Oncology. 2004;67(3-4):277-90.

Upregulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer’s disease. Angulo E, Noe V, Casado V, Mallol J, Gomez-Isla T, Lluis C, Ferrer I, Ciudad CJ, Franco R. Journal of Neurochemistry. (2004) Vol 91: 547-57.

Epicatechin and cocoa polyphenolicextract modulate gene expression in human Caco-2 cells. Noe V, Penuelas S, Lamuela-Raventos RM, Permanyer J, Ciudad CJ, Izquierdo-Pulido M. The Journal of Nutrition. (2004) Vol 134: 2509-16.

Use of siRNAs and antisense oligonucleotides against survivin RNA to inhibit steps leading to tumor angiogenesis. Coma S, Noe V, Lavarino C, Adan J, Rivas M, Lopez-Matas M, Pagan R, Mitjans F, Vilaro S, Piulats J & Ciudad CJ. Oligonucleotides. (2004) Vol 14: 100-13. (Abstract)

Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism. Llaverias G, Vazquez-Carrera M, Sanchez RM, Noe V, Ciudad CJ, Laguna JC & Alegret M. J Lipid Res. (2004) (Abstract) (pdf)

Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages. Llaverias G, Noe V, Penuelas S, Vázquez-Carrera M, Sanchez RM, Laguna JC, Ciudad CJ & Alegret M. Biochem Biophys Res Commun. (2004) Vol 318 :265-74. (Abstract) (pdf)

A novel muscle DNA-binding activity in the GLUT1 promoter. Sanchez-Feutrie M, Santalucia T, Fandos C, Noe V, Viñals F, Brand NJ, Ciudad CJ, Palacin M & Zorzano A. Cell Mol Life Sci. (2004) Vol 61: 709-20. (Abstract)

The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin-dependent kinase inhibitors, S. Peñuelas, C. Alemany, V. Noé & C. Ciudad. European Journal of Biochemistry. (2003) Vol 270: 4809-22 (Abstract) (pdf)

An intron is required for dihydrofolate reductase protein stability. V. Noé, S. MacKenzie & C.J. Ciudad. The Journal of Biological Chemistry. (2003) Vol 278: 38292-300 (Abstract) (pdf)

CD4 Expression Decrease by Antisense Oligonucleotides: Inhibition of Rat T CD4+ Cell Reactivity. M. Rabanal, A. Franch, V. Noé, C.J. Ciudad, C. Castellote & M. Castell. Oligonucleotides. (2003) vol 13:217-28. Abstract

Transcriptional regulation of the human Sp1 gene promoter by SP-family members, NF-Y and E2F.. Marta Nicolás, Vèronique Noé, and Carlos J. Ciudad. Biochemical Journal. (2003) Vol 371:265-75. (Abstract) (pdf)

Inhibition of cd4 expression by antisense oligonucleotides in PMA-treated lymphocytes. M. Rabanal , A. Franch, V. Noé, C. J. Ciudad , M. Castell & C. Castellote - Antisense and Nucleic Acid Drug Development. (2002) Vol 12, 399-410 Abstract

Development and effects of immunoliposomes carrying an antisense oligonucleotide against DHFR RNA and directed toward human breast cancer cells overexpressing HER2. Rodríguez, M.M., Coma, S., Noé, V., & Ciudad, C.J. Antisense & Nucleic Acid Drug Development. (2002) Vol 12: 257 - 264 Abstract

Cloning and characterization of the 5'-flanking region of the human transcription factor Sp1. Nicolas M, Noe V, Jensen KB, Ciudad CJ. J Biol Chem. (2001) Vol 276: 22126-22132 (Abstract) (pdf)

Sp1 involvement in the 4beta-phorbol 12-myristate 13-acetate (TPA)-mediated increase in resistance to methotrexate in Chinese hamster ovary cells. Noe V V, Alemany C, Nicolas M, Ciudad CJ. Eur J Biochem. (2001) Vol 268 :3163-3173. (Abstract) (pdf)

DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. Montell E, Turini M, Marotta M, Roberts M, Noe V, Ciudad CJ, Mace K, Gomez-Foix AM. Am J Physiol Endocrinol Metab (2001) Vol 280 :E229-E237 (Abstract) (pdf)

Differential induction of stearoyl-CoA desaturase and acyl-CoA oxidase genes by fibrates in HepG2 cells. Rodriguez C, Cabrero A, Roglans N, Adzet T, Sanchez RM, Vazquez M, Ciudad CJ, Laguna JC. Biochem Pharmacol (2001) Vol 61 :357-364 (Abstract) (pdf)

Differences in the formation of PPARalpha-RXR/acoPPRE complexes between responsive and nonresponsive species upon fibrate administration. Rodriguez C, Noe V, Cabrero A, Ciudad CJ, Laguna JC. Mol Pharmacol (2000) Vol 58 :185-93 (Abstract) (pdf)

Identification by RNA-based arbitrarily primed PCR of the involvement of cytochrome c oxidase in the development of resistance to methotrexate. C. Alemany, V. Noé, and C.J. Ciudad. Biochim Biophys Acta (2000) Vol 1495 :319-26. (Abstract) (pdf)

Effects of differential polyadenylation and cell growth in dihydrofolate reductase mRNA stability. V Noé, Ciudad, C.J. & Chasin, L.A.J Biol Chem (1999) Vol 274 :27807-14 (Abstract) (pdf)

Effects of antisense oligonucleotides directed toward dihydrofolate reductase RNA in mammalian cultured cells. Rodriguez, M., Noé, V., Alemany, C., Miralles, A., Bemi, V., Caragol, I. and Ciudad, C.J. Int J Cancer (1999) Vol 81 :785-92 (Abstract) (pdf)

Retinoblastoma protein associates with Sp1 and activate the hamster dihydrofolate reductase promoter. Noé, V., Alemany, C., Chasin, L.A. and Ciudad, C.J. Oncogene (1998) Vol 16 :1931-8 (Abstract) (pdf)

Cell growth regulation of the hamster dihydrofolate reductase gene promoter by transcription factor Sp1. Noé, V., Chen, C., Alemany, C., Nicolás, M., Caragol, I., Chasin, L.A., and Ciudad, C.J. Eur J Biochem (1997) Vol 249: 13-20 (Abstract)

Protein kinase C inhibitors reduce phorbol ester-induced resistance to methotrexate in Chinese hamster ovary cells. Noé-V; Ciudad-CJ. Biochem Pharmacol (1995) Vol 50: 337-46 (Abstract) (pdf)

Purine enzyme profile in human colon-carcinoma cell lines and differential sensitivity to deoxycoformycin and 2'-deoxyadenosine in combination. Camici-M; Turriani-M; Tozzi-MG; Turchi-G; Cos-J; Alemany-C; Miralles-A; Noé-V; Ciudad-CJ. Int J Cancer (1995) Vol 62 :176-83 (Abstract)

Determination of dihydrofolate reductase gene amplification from single cell colonies by quantitative polymerase chain reaction.Noé-V; Alemany-C; Ciudad-CJ. Anal Biochem (1995) Vol 224 :600-3 (Abstract) (pdf)

Cytotoxicity of deoxycoformycin on human colon carcinoma cell lines.Camici M, Turriani M, Turchi G, Tozzi MG, Cos J, Alemany C, Noe V, Ciudad CJ. Adv Exp Med Biol (1994) Vol 370: 275-8

Point mutational analysis of the hamster dihydrofolate reductase minimum promoter.Ciudad-CJ; Morris-AE; Jeng-C; Chasin-LA. J Biol Chem (1992) Vol 267: 3650-6 (Abstract)

RNA processing mutants at the dihydrofolate reductase locus in Chinese hamster ovary cells. v Chasin LA, Urlaub G, Mitchell P, Ciudad C, Barth J, Carothers AM, Steigerwalt R, Grunberger D. Prog Clin Biol Res (1990) Vol 340A: 295-304

Nonsense mutations in the dihydrofolate reductase gene affect RNA processing.Urlaub G, Mitchell PJ, Ciudad CJ, Chasin LA. Mol Cell Biol (1989) Vol 9: 2868-80 (Abstract).

Deletion analysis of the Chinese hamster dihydrofolate reductase gene promoter.Ciudad CJ, Urlaub G, Chasin LA. J Biol Chem (1988) Vol 263: 16274-82 (Abstract)

COLLABORATION GROUPS

This group is part of the Consolidated Group "Anticancer, Antiatherosclerotic and Antiinflammatory Therapies" together with the Unit of Pharmacology and the Department of Physiology from the School of Pharmacy, University of Barcelona.

Our group forms part of the "Gene Therapy Network" and "Medical Chemistry" suported by the Generalitat of Catalonia

At the international level, we maintain a stable collaboration with the Department of Biological Sciences.( Columbia University) and Molecular Neuro-Oncology (Rockefeller University), both in New York City.

RESEARCH PROJECTS

Differentially expressed Nodes in Genomic Networks from Methotrexate resistant cells and sensitization by siRNAs; DHFR: regulation by Sp3, Stability of the protein and Gene Therapy. Biomedicine (2006-2008)
Collaborative project with Merck-Farma regarding knock-out of specific genes with pro-angiogenic function (2005)
Genomic profile of methotrexate resistance, molecular mechanisms of DHFR regulation and gene therapy. CICYT (2002-2005)
Collaborative project with Merck-Farma laboratories related with antiangiogenic targets (2004)
Fundació Caixa de Pensions 'La Caixa'; Functional and Molecular interaction of the glutamic and adenosine metabotropic receptors and their role in the Alzheimer disease. Identification of new targets for the diagnostic and therapy of the disease. (2002-2005)
Collaborative project with Nutrexpa laboratories (2002-2003)
Cancer Chemotherapy: Resistance and Lipidic Metabolism. SGR (2002-2005)
Collaborative project with Merck-Farma laboratories related with proapoptotic targets (2001-2002)
Functional genomic study of the effect of statins and PPAR activators on the gene profile induced by oxidized LDL in THP-1 cells. FISss (2001-2003)
Cancer Chemotherapy: Resistance and Lipidic Metabolism. SGR (2000-2002)
Targeting of genes and antisense oligonucleotides by novel liposome formulations: Evaluation of their therapeutic efficacy in human leukemia. JNIC (2000-2003)
Collaborative project with Merck-Farma laboratories (1999-2000)
Transcriptional and postranscriptional regulation of DHFR. Inhibition of the protein by oligonucleotides isolated from combinatorial libraries. CICYT (1999-2002)
Cancer Chemotherapy: Resistance and Lipidic Metabolism. SGR (1998)
Resistance to chemotherapy developed by methotrexate: Molecular mechanisms and modulators. CICYT (1996)
Cancer Chemotherapy: Resistance and Lipidic Metabolism. SGR (1996)
Cancer Chemotherapy: Resistance and Lipidic Metabolism. GRQ (1994)
Cloning of genes responsible for the gene amplification that develops upon cancer chemotherapy. CICYT (1994)
Molecular mechanism of action of deoxycoformycin in tumor cells. CNR (1993)
Regulation of the dhfr gene promoter throughout the cell cycle. Relationship with the gene amplification developed upon methotrexate treatment. FISss (1992)