Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo

Ferrari,Silvia   Martina; Bocci,Guido; Di Desidero,Teresa; Elia,Giusy; Ruffilli,Ilaria; Ragusa,Francesca; Orlandi,Paola; Paparo,Sabrina   Rosaria; Patrizio,Armando; Piaggi,Simona; La Motta,Concettina; Ulisse,Salvatore; Baldini,Enke; Materazzi,Gabriele; Miccoli,Paolo; Antonelli,Alessandro; Fallahi,Poupak

doi:10.3892/or.2018.6306

Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo

Authors:
- Silvia Martina Ferrari
- Guido Bocci
- Teresa Di Desidero
- Giusy Elia
- Ilaria Ruffilli
- Francesca Ragusa
- Paola Orlandi
- Sabrina Rosaria Paparo
- Armando Patrizio
- Simona Piaggi
- Concettina La Motta
- Salvatore Ulisse
- Enke Baldini
- Gabriele Materazzi
- Paolo Miccoli
- Alessandro Antonelli
- Poupak Fallahi
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Affiliations: Department of Clinical and Experimental Medicine, University of Pisa, I-56126 Pisa, Italy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, I-56126 Pisa, Italy, Department of Pharmacy, University of Pisa, I-56126 Pisa, Italy, Department of Surgical Sciences, ‘Sapienza’ University of Rome, I-00161 Rome, Italy, Department of Surgical, Medical and Molecular Pathology and Critical Care, University of Pisa, I-56124 Pisa, Italy
Published online on: March 8, 2018 https://doi.org/10.3892/or.2018.6306
Pages: 2225-2234

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Abstract

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50 passages. The effect of lenvatinib (1 and 100 nM; and 1, 10, 25 and 50 µM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CD nu/nu mice. Lenvatinib significantly reduced ATC cell proliferation (P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion (P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CD nu/nu mice and tumor masses were observed 20 days later. Tumor growth was significantly inhibited by lenvatinib (25 mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications.

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