cAMP analogs as potential therapeutic agents for poorly differentiated thyroid cancer
E Grassi1, A Dicitore2, M Borghi2,1, T de Filippis2, G Vitale1,2 & L Persani1,2
Thyroid cancer is the most common endocrine malignancy characterized by a good prognosis. However, the subgroup of poorly differentiated thyroid carcinomas (PDTCs) includes neoplasia highly aggressive and scarcely responsive to currently available therapies.
Site-selective cAMP analogs are able to inhibit the growth of poorly differentiated solid tumors and may represent valuable candidates for the therapy of PDTCs.
We evaluated the effects of a PKA I-selective cAMP analogs association and another analog (8-Cl-cAMP) on a panel of 6 cell lines from papillary, follicular, poorly differentiated and anaplastic thyroid cancer. The targets of our pharmacological study were modifications of cell-cycle, apoptosis and principal signaling pathways involved in cell proliferation.
8-Cl-cAMP had a significant anti-proliferative effect on all the cell lines tested, with EC50 values between 1.0 and 16.8 μM; PKA I-selective analogs showed a preferential cytostatic action on PDTCs (8505c, HTC-C3 and SW579 cell lines) with an EC50 between 37.2 and 44.5 μM.
In particular, 8-Cl-cAMP was able:
1) to influence cell cycle progression as evidenced by a reduction in the G0/G1 fraction and an accumulation in S phase;
2) to induce apoptosis, as determined by FACS and Annexin V/propidium iodide-staining.
Otherwise, PKA I-selective analogs caused a slight increase in the G0/G1 cell fraction without apoptosis induction. Furthermore, the analysis of intracellular pathways showed that both treatments were able to reduce Akt activation, one of the principal regulator of cell proliferation. Moreover PKA I-selective analogs significantly reduced ERK1/2 activation in SW579 cell line.
In conclusion, 8-Cl-cAMP may represent a powerful broad-spectrum, pro-apoptotic anticancer drug, while PKA I-selective analogs seem to preferentially inhibit undifferentiated cancer cell growth. These studies prompt further in vivo experimentation to test the efficacy and safety of these agents.
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