Abstract 3551: Role of proteasome in the development of multidrug resistance in childhood rhabdomyosarcoma

Abstract

Abstract Multidrug resistance (MDR) is a common problem in the treatment of childhood rhabdomyosarcoma (RMS). The aim of this study was to investigate different mechanism of MDR in childhood RMS and to analyze possible reversal strategies. Female athymic mice underwent xenotransplantation with embryonal (A204) or alveolar (Rh30) RMS cells and were treated with vincristine (0.75 mg/kg/d i.p.). Gene expression analysis with Affymetrix oligonucleotide microarrays HU-Gene 1.0 revealed 2314 differentially expressed genes between the groups in alveolar RMS and 1387 in embryonal RMS. Ingenuity Pathways Analysis of biological pathways and functions of these genes revealed a cluster 21 genes related to the ubiquitin pathway. Among them 4 genes shown an up-regulation and 17 a 0.5 lower expression in vincristine treated samples. Furthermore, among of 45 genes of the proteasome cluster with 35 being down-regulated in RMS from animals treated with vincristine, putative mediating the development of MDR. Changes of gene expression were confirmed by qRT-PCR for selected proteasome components, such as PSMB1, PSMB6 and PSMD14. Specific inhibition of proteasome activity with bortezomib and MG132 inhibits proliferation of RMS cells, but reduces the cytotoxic activity of vincristine in a cell vitality assay. Our results emphasize the role of proteasome in the development of MDR in rhabdomyosarcoma treated with vincristine. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3551.