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.

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This work was partially supported by the Italian Ministry of Education, Research and University (FIRB RBAP11884 M) and by Rusconi Foundation
doi.org/10.1007/s12020-015-0597-7, hdl.handle.net/1765/82233
Endocrine
Department of Internal Medicine

Dicitore, A, Grassi, E.S, Caraglia, M, Borghi, A.M, Gaudenzi, G, Hofland, L.J, … Vitale, G. (2016). The cAMP analogs have potent anti-proliferative effects on medullary thyroid cancer cell lines. Endocrine, 51(1), 101–112. doi:10.1007/s12020-015-0597-7