Abstract
Fusion-positive rhabdomyosarcoma (FP-RMS) is a highly aggressive childhood malignancy which is mainly treated by conventional chemotherapy, surgery and radiation therapy. Since radiotherapy is associated with a high burden of late side effects in pediatric patients, addition of radiosensitizers would be beneficial. Here, we thought to assess the role of fenretinide, a potential agent for FP-RMS treatment, as radiosensitizer. Survival of human FP-RMS cells was assessed after combination therapy with fenretinide and ionizing radiation (IR) by cell viability and clonogenicity assays. Indeed, this was found to significantly reduce cell viability compared to single treatments. Mechanistically, this was accompanied by enhanced production of reactive oxygen species, initiation of cell cycle arrest and induction of apoptosis. Interestingly, the combination treatment also triggered a new form of dynamin-dependent macropinocytosis, which was previously described in fenretinide-only treated cells. Our data suggest that fenretinide acts in combination with IR to induce cell death in FP-RMS cells and therefore might represent a novel radiosensitizer for the treatment of this disease.
Highlights
Radiation therapy (RT) applying ionizing radiation (IR) is, along with chemotherapy and surgery, part of the standard therapeutic regimen for many malignancies
As RT is part of the Fusion-positive rhabdomyosarcoma (FP-RMS) standard treatment regimens, we questioned whether fenretinide would enhance the anti-tumor effect of RT on FP-RMS cells
We further investigated the effect of fenretinide and IR on cell cycle distribution
Summary
Radiation therapy (RT) applying ionizing radiation (IR) is, along with chemotherapy and surgery, part of the standard therapeutic regimen for many malignancies. In the pediatric patient population this treatment is used e.g. in neuroblastoma, medulloblastoma, Ewing and soft tissue sarcomas [1]. Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children and young adolescents. The fusion-positive rhabdomyosarcoma subgroup (FP-RMS) is associated with a poor outcome due to its aggressiveness and a high risk of relapse [2,3,4,5]. The effectiveness of IR is well studied and has direct and indirect effects on cancer cells. IR damages DNA, proteins and lipids, which eventually results in genotoxic stress, cell cycle arrest and cell death [6]. Indirect effects occur through radiolysis of water and the production of reactive oxygen species (ROS). The unpaired electrons in ROS are highly reactive and can induce
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