Abstract

Recent studies have indicated that targeting glutathione-S-transferase (GST) isoenzymes may be a promising novel strategy to improve the efficacy of conventional chemotherapy in the three most common musculoskeletal tumours: osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. By using a panel of 15 drug-sensitive and drug-resistant human osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma cell lines, the efficay of the GST-targeting agent 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has been assessed and related to GST isoenzymes expression (namely GSTP1, GSTA1, GSTM1, and MGST). NBDHEX showed a relevantin vitroactivity on all cell lines, including the drug-resistant ones and those with higher GSTs levels. Thein vitroactivity of NBDHEX was mostly related to cytostatic effects, with a less evident apoptotic induction. NBDHEX positively interacted with doxorubicin, vincristine, cisplatin but showed antagonistic effects with methotrexate. In vivo studies confirmed the cytostatic efficay of NBDHEX and its positive interaction with vincristine in Ewing's sarcoma cells, and also indicated a positive effect against the metastatisation of osteosarcoma cells. The whole body of evidence found in this study indicated that targeting GSTs in osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma may be an interesting new therapeutic option, which can be considered for patients who are scarcely responsive to conventional regimens.

Highlights

  • Osteosarcoma and Ewing’s sarcoma are the two most frequent bone tumours

  • We have demonstrated that overexpression at diagnosis of the glutathione-S-transferase P1 (GSTP1) isoenzyme is associated with a higher relapse rate and a worse prognosis, as a consequence of a reduced responsiveness to conventional treatments [8]

  • The analysis of GST genes expression on cell lines focused on GSTP1, GSTM1, GSTA1 and microsomal glutathione Stransferase (MGST) (Fig. 1A-D)

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Summary

Introduction

Osteosarcoma and Ewing’s sarcoma are the two most frequent bone tumours. These two neoplasms show several differences with respect to their origin and biological and molecular features, they share a similar clinical history. The introduction of chemotherapy has significantly improved the prognosis of osteosarcoma and Ewing’s sarcoma non-metastatic patients, shifting the 5-year survival rate to around 60–65%. Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents, accounting for approximately 5% of all pediatric cancers and 50% of soft tissue sarcomas.

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