Abstract
Background: Papillary Thyroid Carcinoma (PTC) represents the most common thyroid cancer. Until recently, treatment options for PTC patients are limited. Nilotinib is the second-generation tyrosine kinase inhibitor, and has been widely used in the treatment of Chronic Myeloid Leukemia (CML).
Objectives: We aimed to explore whether nilotinib is effective for the suppression PTC cancer progression and the underlying mechanisms.
Methods: In this study, the three human PTC cell lines (KTC-1, BCPAP, and TPC1) were used to verify the effects of nilotinib on cell growth. The half maximal inhibitory concentration (IC50) was calculated according to the growth curve post nilotinib treatment at different concentrations. Cell counting kit-8 and colony formation analysis were used to monitor cell growth after nilotinib treatment. Cell apoptosis and autophagy related proteins and phosphorylation of PI3K/Akt/mTOR were detected by Western blotting analysis.
Results: Nilotinib treatment could effectively inhibit PTC cell growth, which was accompanied by an increase in apoptosis and induction of autophagy. Mechanistically, nilotinib treatment repressed the phosphorylation of the PI3K/Akt/mTOR pathway.
Conclusion: Collectively, our results demonstrated that nilotinib may display anti-tumor effect against PTC via inhibiting PI3K/Akt/mTOR pathway and inducing apoptosis and autophagy.
Keywords: Nilotinib, papillary thyroid carcinoma, PI3K/Akt/mTOR, apoptosis, autophagy, phosphorylation.
Graphical Abstract
[http://dx.doi.org/10.1038/modpathol.2010.129] [PMID: 21455196]
[http://dx.doi.org/10.1001/jama.1976.03270250023018] [PMID: 1036567]
(b) Mazzaferri, E.L.; Jhiang, S.M. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am. J. Med., 1994, 97(5), 418-428.
[http://dx.doi.org/10.1016/0002-9343(94)90321-2] [PMID: 7977430]
[http://dx.doi.org/10.1038/sj.onc.1203957] [PMID: 11114734]
[http://dx.doi.org/10.1124/jpet.105.084145] [PMID: 16002463]
(b) Levitzki, A.; Gazit, A. Tyrosine kinase inhibition: an approach to drug development. Science, 1995, 267(5205), 1782-1788.
[http://dx.doi.org/10.1126/science.7892601] [PMID: 7892601]
[http://dx.doi.org/10.1038/sj.bjc.6603170] [PMID: 16721371]
(b) Quintás-Cardama, A.; Cortes, J. Nilotinib: a phenylamino-pyrimidine derivative with activity against BCR-ABL, KIT and PDGFR kinases. Future Oncol., 2008, 4(5), 611-621.
[http://dx.doi.org/10.2217/14796694.4.5.611] [PMID: 18922118]
[http://dx.doi.org/10.1016/j.bbapap.2009.11.008] [PMID: 19922818]
(b) Tian, X.; Zhang, H.; Heimbach, T.; He, H.; Buchbinder, A.; Aghoghovbia, M.; Hourcade-Potelleret, F. clinical pharmacokinetic and pharmacodynamic overview of nilotinib, a selective tyrosine kinase inhibitor. J. Clin. Pharmacol., 2018, 58(12), 1533-1540.
[http://dx.doi.org/10.1002/jcph.1312] [PMID: 30179260]
[http://dx.doi.org/10.1097/00125480-200111000-00005] [PMID: 11707626]
(b) Kimura, E.T.; Nikiforova, M.N.; Zhu, Z.; Knauf, J.A.; Nikiforov, Y.E.; Fagin, J.A. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res., 2003, 63(7), 1454-1457.
[PMID: 12670889]
[http://dx.doi.org/10.1210/jc.2005-2845] [PMID: 16849418]
(b) Dawson, S.J.; Conus, N.M.; Toner, G.C.; Raleigh, J.M.; Hicks, R.J.; McArthur, G.; Rischin, D. Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma. Anticancer Drugs, 2008, 19(5), 547-552.
[http://dx.doi.org/10.1097/CAD.0b013e3282fc6cf7] [PMID: 18418222]
(c) Sherman, S.I. Targeted therapy of thyroid cancer. Biochem. Pharmacol., 2010, 80(5), 592-601.
[http://dx.doi.org/10.1016/j.bcp.2010.05.003] [PMID: 20471374]
[PMID: 4439480]
[http://dx.doi.org/10.1038/nrclinonc.2009.4] [PMID: 19333228]
[http://dx.doi.org/10.1074/jbc.M112.446385] [PMID: 23677989]
[http://dx.doi.org/10.1016/j.tiv.2015.11.002] [PMID: 26549707]
(b) Silveira, E.; Cavalcante, I.P.; Kremer, J.L.; de Mendonça, P.O.R.; Lotfi, C.F.P. The tyrosine kinase inhibitor nilotinib is more efficient than mitotane in decreasing cell viability in spheroids prepared from adrenocortical carcinoma cells. Cancer Cell Int., 2018, 18(1), 29.
[http://dx.doi.org/10.1186/s12935-018-0527-x] [PMID: 29507530]
[http://dx.doi.org/10.1016/j.gde.2005.11.002] [PMID: 16343892]
[PMID: 19707322]
[http://dx.doi.org/10.1038/leu.2009.45] [PMID: 19262594]
(b) Forchap, S.L.; Pirmohamed, M.; Clark, R.E. Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis. Leukemia, 2012, 26(3), 490-498.
[http://dx.doi.org/10.1038/leu.2011.231] [PMID: 21886172]
[PMID: 3689967]
[http://dx.doi.org/10.1124/mol.114.091850] [PMID: 24574520]
(b) Hippert, M.M.; O’Toole, P.S.; Thorburn, A. Autophagy in cancer: good, bad, or both? Cancer Res., 2006, 66(19), 9349-9351.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1597] [PMID: 17018585]
[http://dx.doi.org/10.4161/cbt.11.2.14663] [PMID: 21263212]
[http://dx.doi.org/10.15252/emmm.201707918] [PMID: 29438985]
[http://dx.doi.org/10.1016/j.ejca.2009.04.030] [PMID: 19467857]
(b) Italiano, A.; Cioffi, A.; Coco, P.; Maki, R.G.; Schöffski, P.; Rutkowski, P.; Le Cesne, A.; Duffaud, F.; Adenis, A.; Isambert, N.; Bompas, E.; Blay, J.Y.; Casali, P.; Keohan, M.L.; Toulmonde, M.; Antonescu, C.R.; Debiec-Rychter, M.; Coindre, J.M.; Bui, B. Patterns of care, prognosis, and survival in patients with metastatic Gastrointestinal Stromal Tumors (GIST) refractory to first-line imatinib and second-line sunitinib. Ann. Surg. Oncol., 2012, 19(5), 1551-1559.
[http://dx.doi.org/10.1245/s10434-011-2120-6] [PMID: 22065192]
[http://dx.doi.org/10.3390/cells8050506] [PMID: 31130711]
[http://dx.doi.org/10.14309/crj.0000000000000003] [PMID: 31616712]
(b) Sasaki, K.; Lahoti, A.; Jabbour, E.; Jain, P.; Pierce, S.; Borthakur, G.; Daver, N.; Kadia, T.; Pemmaraju, N.; Ferrajoli, A.; O’Brien, S.; Kantarjian, H.; Cortes, J. Clinical safety and efficacy of nilotinib or dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia and pre-existing liver and/or renal dysfunction. Clin. Lymphoma Myeloma Leuk., 2016, 16(3), 152-162.
[http://dx.doi.org/10.1016/j.clml.2015.12.003] [PMID: 26796981]
[http://dx.doi.org/10.3892/ijo.2014.2619] [PMID: 25175082]