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

Shu-Fu Lin,Ting-Chao Chou,Richard J Wong,Chuen Hsueh,Jen-Der Lin,Irina V Lebedeva

doi:10.1371/journal.pone.0172315

Shu-Fu Lin, Ting-Chao Chou + Show 4 more

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https://doi.org/10.1371/journal.pone.0172315

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Abstract

BackgroundWe explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer.Materials and methodsSeven 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.ResultsDinaciclib 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.ConclusionsDinaciclib 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.

Highlights

Thyroid cancer is a common endocrine malignancy with an increasing incidence in the past three decades
We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer
The growth of ATC xenograft tumors was retarded in a dose-dependent fashion with daily dinaciclib treatment

Summary

Introduction

Thyroid cancer is a common endocrine malignancy with an increasing incidence in the past three decades. More than 90% patients with thyroid malignancy are PTC and FTC, known as well-differentiated thyroid cancer (WDTC). Patients with WDTC usually survive for more than 10 years following treatment with surgery, radioactive iodine (RAI) and thyroid hormone suppressive or replacement therapy. Some patients who develop metastatic and RAI-refractory WDTC have survival of < 3–5 years [2]. Two multi-kinase inhibitors, sorafenib and lenvatinib, have recently been approved by the U.S Food and Drug Administration for the treatment of metastatic and RAI-refractory WDTC. The therapeutic efficacy of these agents is limited in many patients who eventually develop disease progression and require additional therapy [3,4]. Novel treatments with different therapeutic mechanisms are crucial for improving the outcomes of these patients with refractory thyroid cancer. We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer

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