Cytotoxic Drugs in Combination with the CXCR4 Antagonist AMD3100 As a Potential Treatment Option for Pediatric Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma. The prognosis of advanced stage RMS remains poor, and metastatic invasion is a major cause of treatment failure. Therefore, there is an urgent need for treatment alternatives focusing on metastatic invasion and drug resistance. The stromal cell-derived factor-1 (SDF-1)/chemokine receptor 4 (CXCR4) axis is a crucial factor for metastatic invasion in RMS. Clinical data has revealed that high CXCR4 expression is associated with a poor outcome and a high metastatic rate in several malignancies, including RMS. Thus, targeting CXCR4 in addition to classical chemotherapy may improve the effectiveness of RMS treatment. In the present study, flow cytometry and reverse transcription-quantitative PCR were used to assess the effects of the combined treatment with a CXCR4 antagonist and chemotherapy on CXCR4 expression in the embryonal RMS (RME) cell line RD and in the alveolar RMS (RMA) cell line RH30. The functional effect of CXCR4 expression on the migratory behavior of RMS cells was analyzed using Transwell assays. Treatment with cytotoxic agents modulated CXCR4 expression in RMS cells in a dose-, drug- and cell line dependent manner; however, this was not observed in RD cells with vincristine. The expression levels of CXCR4 significantly increased the migratory behavior of RMA and did not affect RME cell migration towards stromal cell-derived factor-1 alpha (SDF-1 alpha). AMD3100 markedly reduced the migration of RH30 cells in the Transwell assays compared with SDF-1 alpha alone, and the cytotoxic agents doxorubicin and vincristine increased this effect. The results of the combined treatment in RMS cells using the CXCR4 antagonist AMD3100 together with cytotoxic drugs demonstrated that this approach may be a promising alternative for the treatment of advanced stage pediatric RMS. The observed effects of circumventing metastatic invasion and drug resistance should be further investigatedin vivo.