AZD1152 negatively affects the growth of anaplastic thyroid carcinoma cells and enhances the effects of oncolytic virus dl922-947

Abstract

Novel therapeutic approaches are required for the treatment of anaplastic thyroid carcinoma (ATC), an incurable disease resistant to current available therapies. Aurora B is an important mitotic kinase involved in chromosome segregation and cytokinesis. It is overexpressed in many cancers including ATC and represents a potential target for chemotherapy. The effects of AZD1152, a specific Aurora B kinase inhibitor, have been evaluated against ATC, showing G 2 /M accumulation, polyploidy and subsequent cell death by mitotic catastrophe upon drug treatment. Only three administrations of AZD1152 significantly reduced the growth of ATC tumour xenogratfs. Oncolytic viruses in association with other forms of treatment have proven highly promising in preclinical and clinical reports. The oncolytic adenovirus dl922-947 is active against ATC cells, and we have evaluated the effects of the association between AZD1152 and dl922-947. In cells treated with virus and drug, we report additive/synergistic killing effects. Interestingly, the phosphorylation of histone H3 (Ser10), the main Aurora B substrate, is inhibited by dl922-947 in a dose-dependent manner, and completely abolished in association with AZD1152. The combined treatment significantly inhibited the growth of ATC tumour xenografts with respect to single treatments. Our data demonstrate that the Aurora B inhibitor AZD1152, alone or in combination with oncolytic virus dl922-947, could represent a novel therapeutic option for the treatment of ATC.

Ionizing radiation enhances dl922–947-mediated cell death of anaplastic thyroid carcinoma cells

“…However, the treatment with the caspase inhibitor zVAD-fmk was not able to restore cell proliferation, supporting the involvement of other cell death pathways rather than the classical apoptosis. Our results are in agreement with the previous reports suggesting alternative cell death mechanisms induced by dl922-947 (Abou El Hassan et al 2004, Baird et al 2008, Libertini et al 2011.…”

“…It has been proposed that drugs blocking cells in G2 phase could enhance the effects of OVs. Indeed, we have demonstrated that the inhibitor of the mitotic kinase Aurora B, AZD1152, enhances the effects of dl922-947 by inducing a G2 arrest (Libertini et al 2011). Accordingly, the accumulation in G2 phase induced by radiation likely enhances the cytopathic effects of dl922-947.…”

“…It has been reported that drugs that block cells in G2/M or inhibit cytokinesis can enhance OV-mediated cell killing (Seidman et al 2001). For example, we recently demonstrated that the cytopathic effects of dl922-947 are enhanced by the Aurora B inhibitor AZD1152, which induces mitotic arrest, accumulation in G2/M phase, and polyploidy (Libertini et al 2011).…”

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

“…To the best of our knowledge, only one paper has been published reporting the effects of AZD1152 in three of the ATC cell lines evaluated in this study, i.e. CAL62, BHT-101, and 8505C (Libertini et al 2011), and no reports are available on the effects of MLN8237 on ATC cells. The IC 50 obtained by Libertini and colleagues for CAL-62 and 8505C are similar to those calculated by us, while the IC 50 of BHT-101 is significantly lower.…”

Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities

“…Adeno 82,83 measles, 69 herpes simplex, 84,85 and vaccinia viruses 86,87 have been tested in vitro as well as in vivo in mouse explant models (Table 3). Conditionally replicative viruses include those that target cells with specific tumor suppressor pathways that have been [88][89][90] or are directed to negatively impact tumor growth such as targeting of angiogenesis.…”