Seminars Archive

Targeting of cells, cellular compartments and single molecules in the design of bioactive drugs.

Abstract
We will present data on the different experimental strategies of our laboratory finalized to control gene expression by targeting molecules playing critical roles in human pathologies. The strategies will include the transcription factors decoy (TFD) approach (nuclear compartimentalization of the biodrug is needed), the antisense targeting of micro RNAs with antagomirs (cytoplasmic compartimentalization needed), the use of a variety of putative therapeutic drugs targeting several different molecules (DNA, RNA and proteins). These biodrugs are designed to be used for experimental therapy of several human pathologies, including osteoporosis, cancer, cystic fibrosis, thalassemia. As far as osteoporosis, our goal is to inhibit osteoclastogenesis or to induce apoptosis of human osteoclasts; antiproliferative drugs are employed to alter cell cycle of several tumor cell lines; inhibition of the proinflammatory IL-8 and IL-6 release is our objective for the development of drugs inhibiting the pro-inflammatory state of cystic fibrosis; induction of HbF is the strategy of choice for the development of a pharmacological therapy for beta-thalassemia. The intracellular traffic of therapeutic molecules (including gene therapy) is of great importance. In addition, the problems related to the study of imaging (at the cellular of animal mouse level) will be discussed, together with the issue of the delivery to cells/tissues of therapeutic drugs. 1. Bezzerri V, Borgatti M, Nicolis E, Lampronti I, Dechecchi MC, Mancini I, Rizzotti P, Gambari R, Cabrini G. Transcription Factor Oligodeoxynucleotides to NF-{kappa}B Inhibit Transcription of IL-8 in Bronchial Cells. Am J Respir Cell Mol Biol. 2008;39(1):86-96. 2. Borgatti M, Bezzerri V, Mancini I, Nicolis E, Dechecchi MC, Lampronti I, Rizzotti P, Cabrini G, Gambari R. Induction of IL-6 gene expression in a CF bronchial epithelial cell line byPseudomonas aeruginosa is dependent on transcription factors belonging to the Sp1superfamily.Biochem Biophys Res Commun. 2007;357(4):977-83. 3. Fibach E, Bianchi N, Borgatti M, Zuccato C, Finotti A, Lampronti I, Prus E, Mischiati C, Gambari R. Effects of rapamycin on accumulation of alpha-, beta- and gamma-globin mRNAs in erythroid precursor cells from beta-thalassaemia patients. Eur J Haematol. 2006;77(5):437-41. 4. Gambari R and Fibach E. Medicinal Chemistry of Fetal Hemoglobin Inducers for Treatment of beta-Thalassemia. Current Medicinal Chemistry, 14: 199-212. 5. Piva R, Penolazzi L, Lambertini E, Giordano S, Gambari R. Induction of apoptosis of human primary osteoclasts treated with a transcription factor decoy mimicking a promoter region of estrogen receptor ï¿¡. Apoptosis. 2005,10:1079-94. 6. Lampronti I, Bianchi N, Borgatti M, Fibach E, Prus E, Gambari R. Accumulation of gamma-globin mRNA in human erythroid cells treated with angelicin. Eur J Haematol. 2003;71(3):189-95. 7. Fibach E, Bianchi N, Borgatti M, Prus E, Gambari R. Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells. Blood. 2003;102(4):1276-81. 8. Borgatti M, Lampronti I, Romanelli A, Pedone C, Saviano M, Bianchi N, Mischiati C, Gambari R. Transcription factor decoy molecules based on a peptide nucleic acid (PNA)-DNA chimera mimicking Sp1 binding sites. J Biol Chem. 2003, 278(9):7500-9.