A cyclin-dependent kinase inhibitor, dinaciclib in preclinical treatment models of thyroid cancer. Academic Article uri icon

Overview

abstract

  • BACKGROUND: We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer. MATERIALS AND METHODS: Seven cell lines originating from three pathologic types of thyroid cancer (papillary, follicular and anaplastic) were studied. The cytotoxicity of dinaciclib was measured using a lactate dehydrogenase assay. The expression of proteins associated with cell cycle and apoptosis was assessed using Western blot analysis and immunofluorescence microscopy. Cell cycle distribution was measured by flow cytometry and immunofluorescence microscopy. Apoptosis and caspase-3 activity were measured by flow cytometry and fluorometric assay. Mice bearing flank anaplastic thyroid cancer (ATC) were treated with intraperitoneal injections of dinaciclib. RESULTS: Dinaciclib inhibited thyroid cancer cell proliferation in a dose-dependent manner. Dinaciclib had a low median-effect dose (≤ 16.0 nM) to inhibit cell proliferation in seven thyroid cancer cell lines. Dinaciclib decreased CDK1, cyclin B1, and Aurora A expression, induced cell cycle arrest in the G2/M phase, and induced accumulation of prophase mitotic cells. Dinaciclib decreased Mcl-1, Bcl-xL and survivin expression, activated caspase-3 and induced apoptosis. In vivo, the growth of ATC xenograft tumors was retarded in a dose-dependent fashion with daily dinaciclib treatment. Higher-dose dinaciclib (50 mg/kg) caused slight, but significant weight loss, which was absent with lower-dose dinaciclib (40 mg/kg) treatment. CONCLUSIONS: Dinaciclib inhibited thyroid cancer proliferation both in vitro and in vivo. These findings support dinaciclib as a potential drug for further studies in clinical trials for the treatment of patients with refractory thyroid cancer.

publication date

  • February 16, 2017

Research

keywords

  • Adenocarcinoma, Follicular
  • Bridged Bicyclo Compounds, Heterocyclic
  • Carcinoma
  • Carcinoma, Papillary
  • Cyclin-Dependent Kinases
  • Pyridinium Compounds
  • Thyroid Neoplasms

Identity

PubMed Central ID

  • PMC5312924

Scopus Document Identifier

  • 85012966801

Digital Object Identifier (DOI)

  • 10.4103/0976-0105.177703

PubMed ID

  • 28207834

Additional Document Info

volume

  • 12

issue

  • 2