title: The cAMP analogs have potent anti-proliferative effects on medullary thyroid cancer cell lines.
abstract: The oncogenic activation of the rearranged during transfection (RET) proto-oncogene has a main role in the pathogenesis of medullary thyroid cancer (MTC). Several lines of evidence suggest that RET function could be influenced by cyclic AMP (cAMP)-dependent protein kinase A (PKA) activity. We evaluated the in vitro anti-tumor activity of 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) and PKA type I-selective cAMP analogs [equimolar combination of the 8-piperidinoadenosine-3',5'-cyclic monophosphate (8-PIP-cAMP) and 8-hexylaminoadenosine-3',5'-cyclic monophosphate (8-HA-cAMP) in MTC cell lines (TT and MZ-CRC-1)]. 8-Cl-cAMP and the PKA I-selective cAMP analogs showed a potent anti-proliferative effect in both cell lines. In detail, 8-Cl-cAMP blocked significantly the transition of TT cell population from G2/M to G0/G1 phase and from G0/G1 to S phase and of MZ-CRC-1 cells from G0/G1 to S phase. Moreover, 8-Cl-cAMP induced apoptosis in both cell lines, as demonstrated by FACS analysis for annexin V-FITC/propidium iodide, the activation of caspase-3 and PARP cleavage. On the other hand, the only effect induced by PKA I-selective cAMP analogs was a delay in G0/G1-S and S-G2/M progression in TT and MZ-CRC-1 cells, respectively. In conclusion, these data demonstrate that cAMP analogs, particularly 8-Cl-cAMP, significantly suppress in vitro MTC proliferation and provide rationale for a potential clinical use of cAMP analogs in the treatment of advanced MTC.
authors: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy. alessandra.dicitore@libero.it.
authors: Alessandra
authors: A
authors: Dicitore
authors: Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
authors: Elisa Stellaria
authors: ES
authors: Grassi
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors: Michele
authors: M
authors: Caraglia
authors: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy.|Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
authors: Maria Orietta
authors: MO
authors: Borghi
authors: Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
authors: Germano
authors: G
authors: Gaudenzi
authors: Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Leo J
authors: LJ
authors: Hofland
authors: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy.|Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
authors: Luca
authors: L
authors: Persani
authors: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy. giovanni.vitale@unimi.it.|Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy. giovanni.vitale@unimi.it.
authors: Giovanni
authors: G
authors: Vitale
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives / Q000737:chemistry; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000588:Amines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018278:Carcinoma, Neuroendocrine / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D013964:Thyroid Neoplasms / Q000473:pathology*
chemical_list: C000611750:8-hexylaminoadenosine-3',5'-cyclic monophosphate; C000611751:8-piperidinoadenosine-3',5'-cyclic monophosphate; D000588:Amines; D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D010880:Piperidines; D000090063:Proto-Oncogene Mas; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; C007940:hexylamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C075440:8-chloroadenosine
keywords: Apoptosis; Cell cycle; Medullary thyroid cancer; cAMP analogs; cAMP-dependent protein kinase A (PKA) pathway