Abstract
Many human cancers have altered cyclin-dependent kinase activity. Inhibition of cyclin-dependent kinases may arrest cell cycle progression and represents an important strategy in the treatment of malignancies. We evaluated the therapeutic effects of roniciclib, a cyclin-dependent kinase inhibitor, as a treatment for anaplastic thyroid cancer. Roniciclib inhibited anaplastic thyroid cancer cell proliferation in a dose-dependent manner. Roniciclib activated caspase-3 activity and induced apoptosis. Cell cycle progression was arrested in G2/M phase. In vivo, the growth of anaplastic thyroid cancer xenograft tumors was retarded by roniciclib treatment without evidence of toxicity. These data provide a rationale for further clinical evaluation using roniciclib in the treatment of patients with anaplastic thyroid cancer.
Highlights
Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and is typically lethal
We evaluated the therapeutic effects of roniciclib on three ATC cell lines using both in vitro and in vivo assays to assess for clinical applicability
The median-effect dose (Dm) was determined on day 4 (Figure 1B). 8505C cells had the lowest Dm (9.7 ± 0.1 nM), followed by KAT18 (11.3 ± 1.1 nM) and 8305C (16.4 ± 0.8 nM). These cytotoxic effects of roniciclib in three ATC cell lines were confirmed by counting viable cells under the microscope after a four-day therapy (Supplementary Figure 1)
Summary
Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and is typically lethal. ATC is classified as TNM stage IV regardless of tumor burden because of its highly aggressive and lethal nature [4]. Multiple modality treatment, including surgery, external radiotherapy and chemotherapy (including paclitaxel, docetaxel, doxorubicin and cisplatin) is the currently most effective approach to improve local control and survival in patients with ATC confined to the thyroid (stage IVA) or the neck (stage IVB). The 2.5-year survival rate is only 50% using such treatment regimens in this subset of patients [5, 6]. There is no effective treatment for metastatic ATC (stage IVC) that consists of approximately 40-60% of all ATC patients at the time of diagnosis [7,8,9]. Novel therapies with different mechanisms of activity are needed to improve the outcomes of patients with this dismal disease
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