Abstract
BackgroundMedullary thyroid cancer (MTC) is a C-cell neoplasm. Surgery remains its main treatment. Promising therapies based on tyrosine kinase inhibitors demand careful patient selection. We previously observed that two non-steroidal anti-inflammatory drugs (NSAID), indomethacin, celecoxib, and nitric oxide (NO) prevented tumor growth in a model of human MTC cell line (TT) in nude mice.MethodsIn the present study, we tested the NO donor: glyceryl trinitrate (GTN), at pharmacological dose, alone and in combination with each of the two NSAIDs on TT cells. We also assessed the anti-proliferative potential of NO-indomethacin, an indomethacin molecule chemically conjugated with a NO moiety (NCX 530, Nicox SA) on TT cells and indomethacin/GTN association in rMTC 6–23 cells. The anti-tumoral action of the combined sc. injections of GTN with oral delivery of indomethacin was also studied on subcutaneous TT tumors in nude mice. Apoptosis mechanisms were assessed by expression of caspase-3, TAp73α, TAp73α inhibition by siRNA or Annexin V externalisation.ResultsThe two NSAIDs and GTN reduced mitotic activity in TT cells versus control (cell number and PCNA protein expression). The combined treatments amplified the anti-tumor effect of single agents in the two tested cell lines and promoted cell death. Moreover, indomethacin/GTN association stopped the growth of established TT tumors in nude mice. We observed a significant cleavage of full length PARP, a caspase-3 substrate. The cell death appearance was correlated with a two-fold increase in TAp73α expression, with inhibition of apoptosis after TAp73α siRNA addition, demonstrating its crucial role in apoptosis.ConclusionAssociation of NO with NSAID exhibited amplified anti-tumoral effects on in vitro and in vivo MTC models by inducing p73-dependent apoptotic cell death.
Highlights
Medullary thyroid carcinoma (MTC) is a neuroendocrine neoplasm of C cells
We have previously demonstrated that the classical non-steroidal anti-inflammatory drugs (NSAID), indomethacin, reduced the development of xenografted TT tumors induced by injection of human Medullary thyroid cancer (MTC) TT cells in nude mice [9]; indomethacin lowered PGE2 secretion by TT cells
Anti-proliferative effects of glyceryl trinitrate (GTN), NSAID/GTN combinations and nitric oxide (NO)-indomethacin on TT cells As previously reported, we observed that the NSAIDs celecoxib and indomethacin prevented the proliferation of TT cells: the cell number in treated samples was reduced by about 30 % at D2 and day 4 (D4) versus controls (Fig. 1a and b)
Summary
Medullary thyroid carcinoma (MTC) is a neuroendocrine neoplasm of C cells (for reviews see [1, 2]). This cancer releases large amounts of calcitonin (CT) correlated to tumor size [3]. Surgical removal of the thyroid with lymph node dissection is the gold standard curative treatment of MTC. Several tyrosine kinase inhibitors (TKIs) that are notably RET receptor inhibitors are used and under evaluation for patients with advanced MTC with promising results [2, 4]. TKIs vandetanib or cabozantinib can be used as single agent for first line systemic therapy in selected patients with advanced progressive MTC. Medullary thyroid cancer (MTC) is a C-cell neoplasm. We previously observed that two non-steroidal anti-inflammatory drugs (NSAID), indomethacin, celecoxib, and nitric oxide (NO) prevented tumor growth in a model of human MTC cell line (TT) in nude mice
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