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Acta Pharmacol Sin. 2017 Nov;38(11):1533-1542. doi: 10.1038/aps.2017.107. Epub 2017 Aug 10.

Evaluation of in vitro and in vivo activity of a multityrosine kinase inhibitor, AL3810, against human thyroid cancer.

Author information

  • 1College of Pharmacy, Nanchang University, Nanchang 330006, China.
  • 2Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Abstract

Thyroid cancer is the most common type of endocrine neoplasia. Despite recent breakthroughs in treatment of the disease, the treatment of advanced, progressive thyroid cancers remains challenging with limited therapeutic options available. In this study, we evaluated a novel and orally bioavailable small-molecule multiple tyrosine kinases inhibitor, AL3810, in preclinical models of thyroid cancer in vitro and in vivo. AL3810 (2-5 μmol/L) dose-dependently inhibited the proliferation of human thyroid cancer cell lines TT, SW579 and TPC-1 in vitro with IC50 values ranging from 0.59 to 7.03 μmol/L. Specifically, this agent dose-dependently arrested the thyroid cancer cells in the G1 phase and induced apoptosis. Furthermore, AL3810 dose-dependently inhibited the migration and invasion of SW579 and TPC-1 cells in vitro. In SW579 and TT xenograft models, oral administration of AL3810 (5-20 mg·kg-1·d-1) for 21 d potently inhibited the tumor growth; immunohistochemical staining revealed that the antitumor activity of AL3810 was closely correlated with its anti-angiogenesis effect, as evidenced by a dose-dependent reduction of microvessels in tumor tissues. To assess the therapeutic potential of AL3810 in treating thyroid cancer involving RET gene fusion, we showed that AL3810 (1-10 μmol/L) dose-dependently inhibited the proliferation of RET-driven Baf3 cell line Baf3-CCDC6-RET, and the auto-phosphorylation of RET in these cells. Our data suggest that AL3810 is a promising agent for the treatment of thyroid cancer.

PMID:
28795691
PMCID:
PMC5672066
[Available on 2018-11-01]
DOI:
10.1038/aps.2017.107
[PubMed - in process]
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