Role of cAMP analogs in the therapy of medullary thyroid cancer
A Dicitore1, E Grassi2, M Borghi1,2, T de Filippis1, L Hofland3, L Persani1,2 & G Vitale1,2
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor highly resistant to chemo-and radiotherapy. Since several reports showed that cAMP has an antiproliferative effect on different types of solid tumors both in vitro and in vivo, we evaluated the potential anti-neoplastic activity of cAMP analogues (8-Cl-cAMP and the equimolar combination of 8-PIP-cAMP and 8-HA-cAMP) in two MTC cell lines (TT and MZ-CRC-1 that harbor C634W and M918T RET mutations, respectively).
Both 8-Cl-cAMP and 8-PIP-cAMP/8-HA-cAMP significantly inhibited MTC cells in a dose-dependent manner, evaluated by MTT proliferation assay, after 6 days of treatment. Interestingly, the antiproliferative effects for both compounds were more prominent in TT (8-Cl-cAMP: IC50=4.4 μM, maximal inhibition =−75%; 8-PIP-cAMP/8-HA-cAMP: IC50=9.7 μM, maximal inhibition =−70%) than in MZ-CRC-1 cells (8-Cl-cAMP: IC50=8.8 μM, maximal inhibition=−47%; 8-PIP-cAMP/8-HA-cAMP: IC50=12.8 μM, maximal inhibition =−63%).
After 6 days of incubation, 8-Cl-cAMP (25 μM in TT and 50 μM in MZCRC-1) significantly decreased the population of TT and MZCRC-1 cells in S phase, as suggestive for a delay in G0/G1-S phase transit, while there was no significant effect on the cell cycle during incubation with 8-PIP-cAMP/8-HA-cAMP in both cell lines. In addition, 8-Cl-cAMP induced a potent stimulation of apoptosis in TT and MZCRC-1 cells, as determined by Annexin V/propidium iodide staining and flow-cytometric analysis. While, a moderate increase of apoptotic MTC cells was observed during incubation with 8-PIP-cAMP/8-HA-cAMP.
These studies uncover a novel potential role for cAMP analogs in the treatment of MTC, thus prompting further in vivo experimentation on the efficacy and safety of these drugs.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.