Anti-Proliferative Role of the Tyrosine Kinase Inhibitors TKI-258 on Oral Squamous Cell Carcinoma In Vitro

Author(s): Isadora C. Silveira, Anna Cecília D.M. Carneiro, Lorraine S. Hiss, Virgínia O. Crema*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 6 , 2020


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Graphical Abstract:


Abstract:

Background: Identification of the antitumor role of tyrosine kinase inhibitors, such as TKI-258, may lead to novel therapeutics for Oral Squamous Cell Carcinoma (OSCC), which has high mortality rates. TKI-258 blocks Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), and Endothelial Growth Factor Receptor (VEGFRs).

Objective: This study aimed to evaluate the effect of TKI-258 treatment on cell proliferation in SCC-4 cells of OSCC.

Methods: BrdU and KI-67 assays were performed by using SCC-4 cells. Control was compared to 1, 5 and 10μM TKI-258 treatment. Control vehicle was compared to: 60μM LY294002 (LY), 2μM Wortmannin (WTN) and LY+WNT. Moreover, TKI 5μM treatment was compared to: TKI 5μM+LY; TKI 5 μM+WTN; TKI 5μM+LY+WTN. After 6h of treatments, immunofluorescence stained BrdU and KI-67 positive cells. Morphometry of proliferative cells was analyzed considering significance of p<0.05.

Results: BrdU and KI-67 assays results were similar for all experiments. TKI-258 treatment leads to an important reduction in proliferation rate in SCC-4 cells in a concentration dependent manner. As expected, there was a significant reduction in the percentage of proliferative cells that had PI3K inhibited. When compared with TKI 5 treatment, proliferating cells were significantly lower with simultaneous PI3K inhibition.

Conclusion: This study demonstrated that TKI-258 plays an anti-proliferative role on SCC-4 cells of OSCC. It could be interesting to block multiples pathways such as FGFRs, PDGFRs and VEGFRs. Therefore, TKI-258 is a promising option for novel therapeutics for OSCC, especially if associated with PI3K inhibition.

Keywords: BrdU, KI-67, PI3K, oral squamous cell carcinoma, SCC-4, tyrosine kinase inhibitors.

[1]
Thomson, P.J. Perspectives on oral squamous cell carcinoma prevention-proliferation, position, progression and prediction. J. Oral Pathol. Med., 2018, 47(9), 803-807.
[http://dx.doi.org/10.1111/jop.12733] [PMID: 29752860]
[2]
Economopoulou, P.; Perisanidis, C.; Giotakis, E.I.; Psyrri, A. The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications. Ann. Transl. Med., 2016, 4(9), 173.
[http://dx.doi.org/10.21037/atm.2016.03.34] [PMID: 27275486]
[3]
Perri, F.; Muto, P.; Aversa, C.; Daponte, A.; Della Vittoria, G.; Pepe, S.; Caponigro, F. Integrated therapeutic approaches in head and neck cancer: the importance of multidisciplinary team management. Anticancer. Agents Med. Chem., 2013, 13(6), 834-843.
[http://dx.doi.org/10.2174/18715206113139990110] [PMID: 23194421]
[4]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[5]
Hu, H.; Liu, Y.; Jiang, T. Mutation-introduced dimerization of receptor tyrosine kinases: from protein structure aberrations to carcinogenesis. Tumour Biol., 2015, 36(3), 1423-1428.
[http://dx.doi.org/10.1007/s13277-015-3287-4] [PMID: 25750036]
[6]
Gotink, K.J.; Verheul, H.M. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis, 2010, 13(1), 1-14.
[http://dx.doi.org/10.1007/s10456-009-9160-6] [PMID: 20012482]
[7]
Porta, C.; Giglione, P.; Liguigli, W.; Paglino, C. Dovitinib (CHIR258, TKI258): structure, development and preclinical and clinical activity. Future Oncol., 2015, 11(1), 39-50.
[http://dx.doi.org/10.2217/fon.14.208] [PMID: 25572783]
[8]
Xie, X.; Wang, Z.; Chen, F.; Yuan, Y.; Wang, J.; Liu, R.; Chen, Q. Roles of FGFR in oral carcinogenesis. Cell Prolif., 2016, 49(3), 261-269.
[http://dx.doi.org/10.1111/cpr.12260] [PMID: 27218663]
[9]
Cierpikowski, P.; Lis-Nawara, A.; Gajdzis, P.; Bar, J. PDGFRα/HER2 and PDGFRα/p53 co-expression in oral squamous cell carcinoma. Anticancer Res., 2018, 38(2), 795-802.
[PMID: 29374704]
[10]
Pianka, A.; Knösel, T.; Probst, F.A.; Troeltzsch, M.; Woodlock, T.; Otto, S.; Ehrenfeld, M.; Troeltzsch, M. Vascular endothelial growth factor receptor isoforms: are they present in oral squamous cell carcinoma? J. Oral Maxillofac. Surg., 2015, 73(5), 897-904.
[http://dx.doi.org/10.1016/j.joms.2014.12.030] [PMID: 25883000]
[11]
Carneiro, A.C.D.M.; Silveira, I.C.D.; Rezende, A.S.; Silva, B.R.O.; Crema, V.O. Tyrosine kinase inhibitor TKI-258 inhibits cell motility in oral squamous cell carcinoma in vitro. J. Oral Pathol. Med., 2017, 46(7), 484-488.
[http://dx.doi.org/10.1111/jop.12511] [PMID: 27732737]
[12]
Barile, F.A.; Arjun, S.; Hopkinson, D. In vitro cytotoxicity testing: Biological and statistical significance. Toxicol. In Vitro, 1993, 7(2), 111-116.
[http://dx.doi.org/10.1016/0887-2333(93)90120-T] [PMID: 20732178]
[13]
Williams, G.H.; Stoeber, K. The cell cycle and cancer. J. Pathol., 2012, 226(2), 352-364.
[http://dx.doi.org/10.1002/path.3022] [PMID: 21990031]
[14]
Renhowe, P.A.; Pecchi, S.; Shafer, C.M.; Machajewski, T.D.; Jazan, E.M.; Taylor, C.; Antonios-McCrea, W.; McBride, C.M.; Frazier, K.; Wiesmann, M.; Lapointe, G.R.; Feucht, P.H.; Warne, R.L.; Heise, C.C.; Menezes, D.; Aardalen, K.; Ye, H.; He, M.; Le, V.; Vora, J.; Jansen, J.M.; Wernette-Hammond, M.E.; Harris, A.L. Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors. J. Med. Chem., 2009, 52(2), 278-292.
[http://dx.doi.org/10.1021/jm800790t] [PMID: 19113866]
[15]
Ghedini, G.C.; Ronca, R.; Presta, M.; Giacomini, A. Future applications of FGF/FGFR inhibitors in cancer. Expert Rev. Anticancer Ther., 2018, 18(9), 861-872.
[http://dx.doi.org/10.1080/14737140.2018.1491795] [PMID: 29936878]
[16]
Heldin, C.H.; Lennartsson, J.; Westermark, B. Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. J. Intern. Med., 2018, 283(1), 16-44.
[http://dx.doi.org/10.1111/joim.12690] [PMID: 28940884]
[17]
Messina, C.; Buzzatti, G.; Dellepiane, C.; Cavo, A.; Tolomeo, F.; Cattrini, C.; Boccardo, F. Genitourinary tumours in the targeted therapies era: new advances in clinical practice and future perspectives. Anticancer Drugs, 2016, 27(10), 917-943.
[http://dx.doi.org/10.1097/CAD.0000000000000405] [PMID: 27400375]
[18]
Shimizu, A.; Zankov, D.P.; Kurokawa-Seo, M.; Ogita, H. Vascular endothelial growth factor-A exerts diverse cellular effects via small G proteins, Rho and Rap. Int. J. Mol. Sci., 2018, 19(4), E1203
[http://dx.doi.org/10.3390/ijms19041203] [PMID: 29659486]
[19]
Sweeny, L.; Zimmermann, T.M.; Liu, Z.; Rosenthal, E.L. Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts. Oral Oncol., 2012, 48(12), 1242-1249.
[http://dx.doi.org/10.1016/j.oraloncology.2012.06.011] [PMID: 22795534]
[20]
Simpson, D.R.; Mell, L.K.; Cohen, E.E. Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. Oral Oncol., 2015, 51(4), 291-298.
[http://dx.doi.org/10.1016/j.oraloncology.2014.11.012] [PMID: 25532816]
[21]
Martins, F.; de Sousa, S.C.; Dos Santos, E.; Woo, S.B.; Gallottini, M. PI3K-AKT-mTOR pathway proteins are differently expressed in oral carcinogenesis. J. Oral Pathol. Med., 2016, 45(10), 746-752.
[http://dx.doi.org/10.1111/jop.12440] [PMID: 26991907]
[22]
Frankson, R.; Yu, Z.H.; Bai, Y.; Li, Q.; Zhang, R.Y.; Zhang, Z.Y. Therapeutic targeting of oncogenic tyrosine phosphatases. Cancer Res., 2017, 77(21), 5701-5705.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-1510] [PMID: 28855209]
[23]
Li, B.; Li, J.; Xu, W.W.; Guan, X.Y.; Qin, Y.R.; Zhang, L.Y.; Law, S.; Tsao, S.W.; Cheung, A.L. Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway. Oncotarget, 2014, 5(22), 11576-11587.
[http://dx.doi.org/10.18632/oncotarget.2596] [PMID: 25344912]
[24]
Iwase, M.; Yoshiba, S.; Uchid, M.; Takaoka, S.; Kurihara, Y.; Ito, D.; Hatori, M.; Shintani, S. Enhanced susceptibility to apoptosis of oral squamous cell carcinoma cells subjected to combined treatment with anticancer drugs and phosphatidylinositol 3-kinase inhibitors. Int. J. Oncol., 2007, 31(5), 1141-1147.
[PMID: 17912441]
[25]
Brown, K.K.; Toker, A. The phosphoinositide 3-kinase pathway and therapy resistance in cancer. F1000Prime Rep., 2015, 7, 13.
[http://dx.doi.org/10.12703/P7-13] [PMID: 25750731]
[26]
Schäfer, N.; Gielen, G.H.; Kebir, S.; Wieland, A.; Till, A.; Mack, F.; Schaub, C.; Tzaridis, T.; Reinartz, R.; Niessen, M.; Fimmers, R.; Simon, M.; Coch, C.; Fuhrmann, C.; Herrlinger, U.; Scheffler, B.; Glas, M. Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. J. Cancer Res. Clin. Oncol., 2016, 142(7), 1581-1589.
[http://dx.doi.org/10.1007/s00432-016-2161-0] [PMID: 27100354]
[27]
Gerullis, H.; Otto, T.; Ecke, T.H. Targeted agents in second-line bladder cancer therapy. Anticancer Drugs, 2012, 23(10), 1003-1015.
[http://dx.doi.org/10.1097/CAD.0b013e3283582a33] [PMID: 22914698]
[28]
Motzer, R.J.; Porta, C.; Vogelzang, N.J.; Sternberg, C.N.; Szczylik, C.; Zolnierek, J.; Kollmannsberger, C.; Rha, S.Y.; Bjarnason, G.A.; Melichar, B.; De Giorgi, U.; Grünwald, V.; Davis, I.D.; Lee, J.L.; Esteban, E.; Urbanowitz, G.; Cai, C.; Squires, M.; Marker, M.; Shi, M.M.; Escudier, B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol., 2014, 15(3), 286-296.
[http://dx.doi.org/10.1016/S1470-2045(14)70030-0] [PMID: 24556040]
[29]
Zang, C.; Eucker, J.; Habbel, P.; Neumann, C.; Schulz, C.O.; Bangemann, N.; Kissner, L.; Riess, H.; Liu, H. Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer. Cell Cycle, 2015, 14(8), 1291-1299.
[http://dx.doi.org/10.4161/15384101.2014.995050] [PMID: 25714853]
[30]
Liu, J.J.; Duan, R.D. LY294002 enhances boswellic acid-induced apoptosis in colon cancer cells. Anticancer Res., 2009, 29(8), 2987-2991.
[PMID: 19661305]


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Article Details

VOLUME: 20
ISSUE: 6
Year: 2020
Published on: 14 June, 2020
Page: [751 - 755]
Pages: 5
DOI: 10.2174/1871520620666200213110944
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