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

• Published in: Acta pharmacologica Sinica 2017-11, Vol.38 (11), p.1533-1542
• Main Authors: Xie, Qin, Chen, Hui, Ai, Jing, Gao, Ying-lei, Geng, Mei-yu, Ding, Jian, Chen, Yi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Angiogenesis; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Animals; Antitumor activity; Apoptosis; Apoptosis - drug effects; Bioavailability; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Enzyme inhibitors; G1 phase; G1 Phase Cell Cycle Checkpoints - drug effects; Gene fusion; Health risk assessment; Humans; Immunology; Inhibitory Concentration 50; Internal Medicine; Kinases; Medical Microbiology; Medical treatment; Mice, Inbred BALB C; Mice, Nude; Naphthalenes - administration & dosage; Naphthalenes - pharmacology; Neovascularization, Pathologic; Oral administration; Original; original-article; Pharmacology/Toxicology; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-ret - metabolism; Quinolines - administration & dosage; Quinolines - pharmacology; Ret protein; Thyroid cancer; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - enzymology; Thyroid Neoplasms - pathology; Time Factors; Tissues; Tumor Burden - drug effects; Tumor cell lines; Tyrosine; Vaccine; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.107

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 pmol/L）dose-dependently inhibited the proliferation of human thyroid cancer cell lines TT, SW579 and TPC-1 in vitro with IC20 values ranging from 0.59 to 7.03 pmol/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 pmol/L） dosedependently 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.