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Endocrine
Jan, 2016;51 (1): 101-12.

The cAMP analogs have potent anti-proliferative effects on medullary thyroid cancer cell lines.

Alessandra Dicitore, Elisa Stellaria Grassi, Michele Caraglia, Maria Orietta Borghi, Germano Gaudenzi, Leo J Hofland, Luca Persani, Giovanni Vitale
Author Information
  1. Alessandra Dicitore: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy. alessandra.dicitore@libero.it.
  2. Elisa Stellaria Grassi: Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
  3. Michele Caraglia: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
  4. Maria Orietta Borghi: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy.
  5. Germano Gaudenzi: Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
  6. Leo J Hofland: Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
  7. Luca Persani: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy.
  8. Giovanni Vitale: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy. giovanni.vitale@unimi.it.
PMID: 25863490 DOI: 10.1007/s12020-015-0597-7

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.

Keywords

Apoptosis Cell cycle Medullary thyroid cancer cAMP analogs cAMP-dependent protein kinase A (PKA) pathway

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MeSH Term

2-Chloroadenosine
8-Bromo Cyclic Adenosine Monophosphate
Amines
Antineoplastic Agents
Apoptosis
Carcinoma, Neuroendocrine
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Humans
MAP Kinase Signaling System
Piperidines
Proto-Oncogene Mas
Thyroid Neoplasms

Chemicals

8-hexylaminoadenosine-3',5'-cyclic monophosphate
8-piperidinoadenosine-3',5'-cyclic monophosphate
Amines
Antineoplastic Agents
MAS1 protein, human
Piperidines
Proto-Oncogene Mas
2-Chloroadenosine
8-Bromo Cyclic Adenosine Monophosphate
8-chloro-cyclic adenosine monophosphate
hexylamine
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
8-chloroadenosine
Journal Article Research Support, Non-U.S. Gov't

Word Cloud

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