OBJECTIVES

The Molecular Pharmacology and Oncology Laboratory seeks to describe and validate new therapeutic targets for cancer treatment with the purpose of developing highly selective and effective novel pharmacological prototypes through a rational design. The laboratory transfers knowledge to several national and international groups through academic and scientific collaborations. The ultimate aim of this interdisciplinary work is to transfer genuine knowledge and highly qualified human resources for the good of national public health, education, science and technology.

MEMBERS

CARLOS DAVIO

Pharmacology Professor, FFyB, UBA and CONICET Principal Investigator

JULIETA IMPERIALE

CONICET Assistant Investigator

JUAN PABLO RODRÍGUEZ

CONICET Assistant Investigator

AGUSTIN YANEFF

CONICET Assistant Investigator

ANA SAHORES

CONICET Postdoctoral researcher

NICOLAS DI SIERVI

CONICET PhD student/fellow

AGUSTIN ISIDRO ALONSO

CONICET PhD student/fellow

SAMANTA GANCEDO

CONICET PhD student/fellow

RESEARCH LINES

THE RELEVANCE OF CAMP, ITS SIGNALING CASCADE, AND THE BALANCE BETWEEN INTRACELLULAR AND EXTRACELLULAR CAMP LEVELS IN CANCER PROGRESSION: THERAPEUTIC IMPLICATIONS AND FUTURE STUDIES.

Science, technology and innovation have an impact on all daily activities (including economics, education, health, employment, services, etc), are powerful means to solve personal issues and allow governments to efficiently diagnose, formulate and apply high-impact social and economic policies.

The validation of a therapeutic target can only be achieved building on previous knowledge. In our project, we propose that the cAMP signaling cascade is an exploitable therapeutic target in cancer. cAMP was the first second messenger described and decisive for the beginning of the signaling transduction era. Shortly after its discovery, Nobel-Award-winner PhD. Sutherland described that this cyclic nucleotide could be transported to the extracellular compartment by an ATP-dependent mechanism. In the last decade, the cAMP underlying transport mechanism was comprehended, being the Multidrug Resistant Proteins, mainly MRP4, responsible for this efflux. In recent years, MRP4 expression was proposed as a prognosis biomarker in different types of cancers and associated to oncogenes which have been traditionally linked to malignant transformation. Our findings have allowed us to redefine MRP4 as a key regulator of the balance between intracellular and extracellular cAMP levels, which may finally affect cancer cell differentiation and proliferation. MRP4 also transports xenobiotics, many of which are clinically used antitumor drugs, and several endobiotic compounds, such as prostaglandins and leukotrienes, are fundamental actors in the inflammatory process. cAMP stability and its elevated plasmatic levels in hyper-proliferative processes postulate this cyclic nucleotide as an easy-detectable biomarker that could help physicians predict poor prognosis and/or monitor therapeutic response. Recent findings from our laboratory involving in silico analysis and experimental results, together with recent publications, show that the dysregulation of MRP4 expression is associated with several pathways related to cell proliferation. cAMP temporal tone depends on MRP4 activity, G protein-coupled receptors (GPCRs), G protein itself and phosphodiesterases, among others. Our main aim is to study, through an interdisciplinary approach, the cAMP signaling cascade and its related pathways, with the final purpose of identifying and validating key components as anticancer therapeutic candidates. Our working group is part of a research consortium which involves biomedical investigators with various professional backgrounds, such as molecular pharmacologists and biologists, chemical physiologists, clinical and molecular oncologists, biostatistics, bioinformatics and pathologists, among others. We are currently studying several types of cancer, including leukemias, pancreatic ductal-adeno-carcinomas (PDAC), clear cell renal cell carcinomas (CCRCC), and colorectal and breast cancers.

RECENT PUBLICATIONS

International Journals with review

  1. Altered expression of Aquaporin-2 in one-kidney, one-clip hypertension. Albertoni Borghese MF., Hope S., Ortiz MC., Barchuk M., Kessler C., DavioC., Vatta M., Majowicz M. Life Sciences 2018, 208:72–78. ISSN 0024-3205 FI2017234
  2. Unique pharmacological properties of serotonergic G-protein coupled receptors from cestodes. Camicia, F., Celentano, A.M., Johns, M.E., Chan, J.D., Maldonado, L., Vaca, H., Di Siervi, N., Kamentezky, L., Gamo, A.M., Ortega-Gutierrez, S., Martin-Fontecha, M., Davio, C., Marchant, S., and Rosenzvit, M. PLOS Neglected Tropical Diseases, 2018, 12(2):e0006267. doi: 10.1371/journal.pntd.0006267. ISSN 1935-2727 FI2016 3.834
  3. MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine substrate binding sites as a tool for drug design. Yaneff, A., Sahores, A., Gómez N., Carozzo A., Shayo C. and Davio C. Curr Med Chem., doi: 10.2174/0929867325666171229133259.  ISSN 0929-8673 FI2016 3.249
  4. Synthesis and degradation of cAMP in Giardia lamblia: Possible role and characterization of a Nucleotidyl Cyclase with a single Cyclase-Homology-Domain. Vanina Saraullo, Nicolas Di Siervi, Belen Jerez, Carlos Davio, Adolfo Zurita. Biochem J., 2017. 474(23):4001-4017. doi: 10.1042/BCJ20170590. ISSN 0264-6021 FI2016 797
  5. Effect of mutation of Phe 24344 of the histamine H2 receptor on cimetidine mechanism of action. Granja-Galeano Gina, Zappia Carlos Daniel, Lucas Fabián, Davio Carlos, Shayo Carina, Fernández Natalia, Monczor Federico. Biochem Pharmacol., 2017. 146:117–126. doi: 10.1016/j.bcp.2017.09.014. ISSN 0006-2952 FI2016 4.581.
  6. Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines. Cabrera M, Echeverria E, Remes Lenicov F, Cardama GA, Gonzalez N, Davio C, Fernández NC*, Lorenzano Menna P*. Oncotarget, 2017. doi: 10.18632/oncotarget.21533. ISSN 1949-2553 FI2016168.
  7. Extracellular cAMP activates molecular signalling pathways associated with sperm capacitation in bovines. Alonso CAI, Osycka-Salut C, Castellano L, Cesari A, Di Siervi N, Mutto A, Johannisson A, Morrell JM, Davio C, Perez-Martinez S. Mol Hum Reprod. 23(8):521-534, 2017 doi: 10.1093/molehr/gax030. ISSN 1360-9947 FI2016 3.585. (*) Davio C and Perez Martinez S. contributed equally to the supervision and financial support of this study.
  8. Evidence for CB2 receptor involvement in LPS-induced reduction of cAMP intracellualar levels in uterine explants from pregnant mice: pathophysiological implications. Ana Inés Salazar, Alejandro Carozzo, Fernando Correa, Carlos Davio*, Ana María Franchi* Mol Hum Reproduction. 23(7):500-508, 2017. doi: 10.1093/molehr/gax026. ISSN 1360-9947 FI2016 585. (*) Carlos Davio and Ana Franchi contributed equally to the supervision and financial support of this study.
  9. Endogenous lysophosphatidic acid participates in vascularization and decidualization at the maternal-fetal interface in the rat. Micaela Sordelli, Jimena Beltrame, Elsa Zotta, Natalia Gomez, Ganna Dmytrenko, Maria Sales, Sandra Blois, Carlos Davio, Silvina Perez Martinez, Ana Franchi andMaria Ribeiro.   Reprod  Fertil Dev. doi: 10.1071/RD16235, ISSN 1031-3613, FI2016 2.656.
  10. Melanocortin 4 receptor constituvie activity inhibits L-type voltage-gated calcium channels in neurons.  Agosti F, Cordisco Gonzalez S, Martinez Damonte V, Tolosa MJ, Di Siervi N, Schioth HB, Davio C, Perello M, Raingo J. Neuroscience , 2017. 346:102-112. doi: 10.1016/j.neuroscience.2017.01.007. ISSN 0306-4522, FI2015 3.321
  11. A Novel Effect of β-Adrenergic Receptor on Mammary Branching Morphogenesis and its Possible Implications in Breast Cancer. Gargiulo L, May M, Rivero EM, Copsel S, Lamb C, Lydon J, Davio C, Lanari C, Lüthy IA, Bruzzone A. J Mammary Gland Biol Neoplasia.  2017. 1:43-57. doi: 10.1007/s10911-017-9371-1. ISSN 1083-3021, FI2015 3.143
  12. Heparin exerts anti-apoptotic effects on uterine explants by targeting the endocannabioid system.Ana Inés Salazar, Claudia Vercelli,, Victoria Schiariti, Carlos Davio, Fernando Correa, Ana María Franchi. Apoptosis, 9:965-76, 2016, ISNN 1360-8185, FI2015 592
  13. PI3K pathway is involved in ERK signaling cascade activation by histamine H2R agonist in HEK293T cells. Alonso Natalia, Diaz Nebreda Antonela, Monczor Federico, Gutkind J. Silvio, Davio Carlos, Fernandez Natalia, Shayo Carina. BBA General Subjet, 1860:1998-2007, 2016, ISNN 0304-4165,FI2015 381
  14. Role of 3'-5'-cyclic adenosine monophosphate on the epidermal growth factor dependent survival in mammary epithelial cells. Diego Y. Grinman, Leonardo Romorini, Diego M. Presman, Luciana Rocha Viegas, Omar A. Coso, Carlos Davio, Adali Pecci. Mol Cell Endocrinol, ,419:259-267, 2016, ISNN 0303-7207 FI2014 405
  15. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Carlos Daniel Zappia, Gina Granja Galeano, Natalia Fernández, Carina Shayo, Carlos Davio, Carlos Fitzsimons, Federico Monczor.  Rep. 5, 17476; doi:10.1038/srep17476, 2015, ISNN 2045-2322 FI2014 5.578
  16. G2/M cell cycle arrest and tumor selective apoptosis of acute leukemia cells by a promising benzophenone thiosemicarbazone compound. Cabrera M, Gomez N, Remes Lenicov F, Echeverría E, Shayo C, Moglioni A, Fernández N, Davio C.Plos One, 2015, 10(9):e0136878. doi: 10.1371/journal.pone.013687. ISSN 1932-6203 FI2014 234
  17. Physiological implications of biased signaling at histamine H2 receptors.  Natalia Alonso, Carlos Daniel Zappia, Maia Cabrera, Carlos Davio, Carina Shayo, Federico Monczor, Natalia Cristina Fernandez.  Pharmacol. 2015, 6:45. doi: 10.3389. ISSN: 1663-9812. FI2014 3.80.
  18. Dual role of cAMP in the transcriptional regulation of multidrug resistance-associated protein 4 (MRP4) in pancreatic adenocarcinoma cell lines. Alejandro Carozzo, Federico Diez, Natalia Gomez, Maia Cabrera, Carina Shayo, Carlos Davio, Natalia Fernández. Plos One,2015, 10(3):e0120651. doi: 10.1371/journal.pone.0120651. ISSN 1932-6203 FI2014 234
  19. Blockade of multidrug resistance associated proteins aggravates acute pancreatitis and blunts atrial natriuretic factor beneficial effect in rats: Role of MRP4/ABCC4. María Silvia Ventimiglia, Ana Clara Najenson, Juan Carlos Perazzo, Alejandro Carozzo, Marcelo S. Vatta, Carlos A. Davio*, Liliana G. Bianciotti*. Mol Med.2015, 21:58-67 doi: 10.2119 ISSN 1076-1551 FI2014508 *contributed equally to this study.
  20. Differential β2-adrenergic receptor expression defines the phenotype of non-tumorigenic and malignant human breast cell lines. L Gargiulo#, S Copsel#, E M Rivero, C Galés, J-M Senard, I A Lüthy, C Davio*,A Bruzzone*. Oncotarget 5(20):10058-69.  ISSN 1949-2553 FI2013 6.359. # and * contributed equally to this study.
  21. Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia. Sabrina Copsel, Ariana Bruzzone, Maria May, Julien Beyrath, Victoria Wargo, Jeannette Cany, Frans G.M. Russel, Carina Shayo, Carlos Davio.Oncotarget 5(19):9308-21.  ISSN 1949-2553 FI2014 6.359.
  22. G protein-coupled receptor30–adenylyl cyclase–protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis. Andrés E. Zucchetti, Ismael R. Barosso, Andrea C. Boaglio, Cecilia L. Basiglio, Diego R. Taborda, Marcelo G. Luquita, Carlos A. Davio, Marcelo G. Roma, Fernando A. Crocenzi, Enrique J. Sánchez Pozzi. 59:1016-1029. 2014. ISSN 0270-9139 FI2014 11.056.
  23. Signal transduction mechanism of biased ligands at histamine H2 receptors. Alonso N, Monczor F, Echeverría E, Davio C, Shayo C, Fernandez N. Biochem J. 459 (1):117-126. 2014. ISSN 0264-6021 FI2012 654
  24. Cyclic AMP efflux through MRPs is critical in the regulation of bovine sperm capacitation: contribution of A1 adenosine receptors. Claudia Osycka Salut#, Federico Diez#, Burdet Juliana, Maria Gracia Gervasi, Ana Franchi, Liliana G Bianciotti, Carlos Davio*and Silvina Perez-Martinez*. (#) Claudia Osycka Salut and Federico Diez contributed equally to this study. (*)Corresponding authors. Mol Hum Reproduction. 20(1):89-99. 2014. ISSN 1360-9947 FI2012542. Editor's highlight. Professor Christopher Barratt, Editor-in-Chief.
  25. Antihistaminergics and inverse agonism. Potential therapeutic applications. Federico Monczor, Natalia Fernandez, Carlos P. Fitzsimons, Carina Shayo, Carlos Davio. Eur J Pharmacol.715:26-32. 2013. ISSN 0014-2999 FI2011516.
  26. Pharmacodynamic study of the 7,8-dihydroxy-4-methylcoumarin-induced selective cytotoxicity towards U-937 leukemic cells versus mature monocytes: cytoplasmic p21Cip1/WAF1 as resistance factor. Vázquez R, Riveiro ME, Mondillo C, Perazzo JC, Vermeulen M, Baldi A, Davio C*,Shayo C*. Biochem Pharmacol, 86(2):210-21, 2013. ISSN 0006-2952 FI201258. *These authors contributed equally to the direction of the study.
  27. On the role of ATP release, ectoATPase activity and extracellular ADP in the regulatory volume decrease of Huh-7 human hepatoma cells. Espelt MV, de Tezanos Pinto F, Alvarez CL, Sanchez Alberti G, Incicco J, Leal Denis MF, Davio C, Schwarzbaum PJ. Am J Physiol Cell Physiol.304(10):1013-1026. ISSN 0363-6143 FI2011 3.54.
  28. Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration. Alonso N, Fernandez N, Notcovich C, Monczor F, Simaan M, Baldi A, Gutkind JS, Davio C, Shayo C. Mol Pharmacol.83(5):1087-98. ISSN 0026-895X FI2012 4.41
  29. Semen promotes the differentiation of tolerogenic dendritic cells. Remes Lenicov, F., Rodriguez Rodrigues, C., Sabatté, J, Cabrini, M., Jancic, C., Ostrowski, M., Merloti, A., Gonzalez, H., Donaldson, M., Pasqualini, R.S., Davio, C., Geffner, J., Ceballos, A. J Immunol. 189(10):4777-86.ISSN 0022-1767 FI2011 5.788
  30. Structure-anti-leukemic activity relationship study of ortho-dihydroxycoumarins in U-937 cells: key role of the δ-lactone ring in determining differentiation-inducing potency and selective pro-apoptotic action. Ramiro Vázquez, María E. Riveiro, Mónica Vermeulen, Eliana Alonso, Carolina Mondillo, Natalia Gómez, Graciela Facorro, Lidia Piehl, Albertina Moglioni, Natalia Fernández, Alberto Baldi, Carina Shayo, Carlos Davio. Bioorg Med Chem. 20(18):5537-49. 2ISSN 0968-0896 FI2011 2.921
  31. Iron and holotransferrin induce cAMP-dependent differentiation of Schwann cells. Carolina Salis; Carlos Davio; Vanina Usach; Nicolas Urtasun; Belen Goitia; Rocio, Martinez Vivot; Juana M Pasquini; Patricia Setton-Avruj. Neurochemistry International 61(5):798-806. 2012. ISSN 0197-0186 IF2011 857
  32. Toddaculin, a natural coumarin from Toddalia asiatica, induces differentiation and apoptosis through different signaling pathways in U-937 leukemic cells. Ramiro Vázquez, María E. Riveiro, Mónica Vermeulen, Carolina Mondillo, Philip H. Coombes, Neal Crouch, Fathima Ismail, Dulcie A. Mulholland, Alberto Baldi, Carina Shayo, Carlos Davio. Phytomedicine.19(8-9):737-46. 2012. ISSN 0944-7113 IF2011268
  33. ALAS-1 gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FOXO1 by vanadate in diabetic mice. Oliveri LM, Davio C, Batlle AM, Gerez EN. Biochem J. 442(2):303-10, 2012. ISSN 0264-6021 FI2011 897
  34. Roles of phosphorylation dependent and independent mechanisms in the regulation of Histamine H2 receptor by G Protein-coupled Receptor Kinase. Fernandez N, Gottardo F, Alonso N, Monczor F, Shayo C, Davio C.J Biol Chem. 286(33):28697-706, 2011. ISSN 0021-9258 FI2011 773
  35. Synthesis, structural characterization and proapoptotic activity of 1-indanone thiosemicarbazones platinum (II) and palladium (II) complexes: Potential role as selective antileukemic agents. Natalia Gómez, Diego Santos, Ramiro Vázquez, Leopoldo Suescun, Álvaro Mombrú, Monica Vermeulen, Liliana Finkielsztein, Carina Shayo, Albertina Moglioni, Dinorah Gambino, Carlos Davio.ChemMedChem, 6(8):1485-94, 2011. ISSN 1860-7179 FI2011151
  36. Atrial natriuretic factor stimulates cAMP efflux in the rat exocrine pancreas through Multidrug Resistance Associated Proteins. Rodriguez M#, Diez F#; Ventimiglia MS, Morales VP, Copsel S, Vatta MS, Davio C*, Bianciotti, LG*. Gastroenterology. 140(4): 1292-1302, 2011. ISSN 0016-5085 FI2011675. # and * contributed equally to this study.
  37. Multidrug Resistance Protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. Copsel S, Garcia C, Diez F, Vermeulem M, Baldi A, Bianciotti LG, Russel FGM, Shayo C and Davio C. J Biol Chem. 286(9):6979–6988, 2011. ISSN 0021-9258 FI2011 773
  38. Endothelins participate in the central and peripheral regulation of submandibular gland secretion in the rat. Maria Ventimiglia, Myrian Rodriguez, Vanina Morales, Juan Elverdin, Juan Perazzo, Mauricio Castañeda, Carlos Davio, Marcelo Vatta, and Liliana Bianciotti. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology. 300(1):R109-20. 2011. ISSN 0363-6119 FI2011 336

Relevant previous publications

  1. Coumarins: Old compounds with novel promising therapeutic perspectives, ME. Riveiro, N. De Kimpe, A. Moglioni, R. Vázquez, F. Monczor, C. Shayo,  Davio. Curr Med Chem17(13):1325-1338. 2010. ISSN 0929-8673 FI2010 4.63
  2. Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein. Fitzsimons CP, Monczor F, Fernandez N, Shayo C, Davio C. J Biol Chem.279(33):34431-9.  ISSN 0021-9258 FI 2004 6.355.
  3. Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model. Monczor F, Fernandez N, Legnazzi BL, Riveiro ME, Baldi A, Shayo C, Davio C.Mol Pharmacol. 64(2):512-520. 2003. ISSN 0026-895X FI200365.
  4. Reduction of G protein-coupled receptor kinase 2 expression in U-937 cells attenuates H2 histamine receptor desensitization and induces cell maturation. Fernandez N, Monczor F, Lemos B, Notcovich C, Baldi A, Davio C, Shayo C. Mol Pharmacol. 62(6):1506-1514. 2002. ISSN 0026-895X FI200248
  5. Histamine H2 receptor desensitization: involvement of a select array of G protein-coupled receptor kinases. Shayo C, Fernandez N, Legnazzi BL, Monczor F, Mladovan A, Baldi A, Davio C. Mol Pharmacol. 60(5):1049-1056. 2001. ISSN 0026-895X FI200145.

International book chapters with review (recent years)

  1. Histamine H2 Receptor in Blood Cells: A Suitable Target for the Treatment of Acute Myeloid Leukemia. Federico Monczor, Sabrina Copsel, Natalia Fernandez, Carlos Davio, and Carina Shayo. Handbook of Experimental Pharmacology, Springer International Publishing Switzerland. 2017. 241:141-160. doi: 10.1007/164_2016_8
  2. Histamine H2 Receptor Biased Signaling Methods. Natalia Fernández, Shayo Carina, Davio Carlos, Monczor Federico. Pag. 67-114. (517 totales). Methods in Pharmacology and Toxicology. Histamine Receptors as Drug Targets. Editores Tiligada, Ekaterini andEnnis, Madeleine. ISBN 978-1-4939-6843-5. Springer International Publishing AG.

FUNDING

  1. Agencia de Promoción Científica y Tecnológica - PICT-2015-2996 (2016-2019) - “RELEVANCIA DEL AMPc Y SU CASCADA DE SEÑALIZACIÓN EN LA PROGRESIÓN DEL CÁNCER DE PÁNCREAS: IMPLICANCIAS TERAPÉUTICAS Y DIRECCIONES FUTURAS”. I.Responsable: Dr. Carlos Davio.
  2. Universidad de Buenos Aires - UBACYT-20020170100674BA (2018-2021) - “MRP4/ABCC4, como nuevo blanco terapeutico en Adenocarcinoma ductal pancreatico”. Director: Dr. Carlos Davio - Responsable de grupo: Dr. Agustín Yaneff y Dra. Carolina Ghanem.
  3. PUE-0045- CONICET - 2017 - "Aproximacion interdisciplinaria para el desarrollo y la optimizacion de aplicaciones farmacologicas en terapias dirigidas a cancer de pancreas y vesicula y rutas biliares: validacion de blancos terapeuticos, diseño y optimizacion racional de drogas". Investigador principal: Dr. Carlos Davio.