Modulation of multidrug-resistance-associated P-glycoprotein in human U-87 MG and HUV-ECC cells with antisense oligodeoxynucleotides to MDR1 mRNA.

摘要

OBJECTIVE: Glioblastoma is the highest dedifferentiated form of astrocytic brain tumors, and it is refractory to chemotherapy in most cases. To improve the clinical outcome of such tumors, new therapeutic strategies are needed. While malignancy is mainly associated with a nonfunctional apoptotic pathway, the lack of chemotherapeutic success correlates with overexpression of the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Previous investigations have shown that not only glioblastoma cells but also endothelial cells are important in the response to chemotherapy. The aim of the present investigations was to reduce the expression of P-gp in the human glioblastoma cell line U-87 MG and in the human endothelial cell line HUV-ECC. METHODS: Therefore, these cells were treated with antisense oligodeoxynucleotides (asn-ODN) directed against the P-gp mRNA in order to increase the intracellular retention of doxorubicin (DOX) which had been given previously. RESULTS: Flow cytometry revealed about 4-fold increased intracellular retention of DOX in both asn-ODN-treated cell lines as compared to asn-ODN non-treated cell lines. CONCLUSION: These results suggest that asn-ODN-mediated inhibition of P-gp expression is an efficient way to increase intracellular retention of DOX.