Abstract
There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma. XI-006 treatment of Ewing and osteosarcoma cell lines (n = 11) resulted in rapid and potent apoptosis at low micro-molar concentrations specifically in Ewing sarcoma cell lines (48 hr IC50 0.099–1.61 μM). Unexpectedly, apoptotic response was not dependent on MDM4 mRNA/protein levels or TP53 status. Alkaline/neutral comet and γH2AX immunofluorescence assays revealed that the cytotoxic effects of XI-006 could not be attributed to the induction of DNA damage. RNA expression analysis revealed that the mechanism of action of XI-006 could be accredited to the inhibition of cell division and cycle regulators such as KIF20A and GPSM2. Finally, potent synergy between XI-006 and olaparib (PARP inhibitor) were observed due to the down-regulation of Mre11. Our findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma.
Highlights
Sarcomas are a group of rare malignancies that affect approximately 200,000 individuals worldwide each year[1]
MDM4 protein expression in a cohort of 36 sarcoma samples of varying histopathology was determined through immunohistochemical analysis (IHC)
As MDM4 gene amplification is a characteristic of both Ewing and osteosarcoma[8], this study assessed the therapeutic potential of XI-006, a small molecule thought to attenuate MDM4 promoter activity, for the treatment of sarcoma
Summary
Sarcomas are a group of rare malignancies that affect approximately 200,000 individuals worldwide each year[1]. With the exception of gastrointestinal stromal tumours (GIST), limited progress in the management of sarcomas has been achieved over the past few decades years For this reason, the advent of novel and targeted therapeutics with favourable efficacy and toxicity profiles are eagerly awaited, especially for those 20–40% of patients with non-responding, unresectable or metastatic disease. Small molecules are considered more desirable for cancer therapy as their cellular uptake is dependent on passive diffusion, whereas stapled peptides such as SAH-p53-8 require pinocytosis, which is less effective[15] This is highlighted by the fact that high concentrations of SAH-p53-8 (15– 30 μ M) were required to induce significant cytotoxicity in melanoma cells in vitro, uptake was attenuated in the presence of serum, and complete regression of xenograft tumours was not achieved[4,16]. Treatment of Ewing sarcoma cell lines resulted in potent apoptosis that was remarkably not dependent on MDM4 mRNA or protein levels or TP53 status
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