Reversal of Doxorubicin Resistance in Human Breast Adenocarcinoma (MCF- 7) Cells by Liposomal Monensin

摘要

We have previously demonstrated that stealth monensin liposomes (SML) prepared by pH-gradient method enhance the cytotoxicity of doxorubicin by a factor of 16.5 in MCF-7/dox cells. There was increase in MDR-1 and MRP-1 mRNA expression as a result of doxorubicin treatment, which was lowered by combination with SML. In the present study, enhancement of cytotoxic drugs by SML was reinvestigated. It showed that paclitaxel, etoposide and doxorubicin showed 2.8, 5.6 and 16.5 fold increase in cell kill in combination with SML. Caspase-3 assay to confirm apoptosis showed that, doxorubicin increased caspase- 3 activity over control, but in combination with SML the activity was further increased by 2.1 fold. Fluorescence studies indicated that doxorubicin uptake was increased as a result of SML treatment. Also our studies indicated that the SML treatment lowered the efflux of doxorubicin from MCF-7/dox cells. Finally in vivo animal experiments were conducted where nulnu mice were xenografted with MCF-7 cells. A group of animals received doxorubicin Smg/kg i.v., while another group received SML (10-6 M) + doxorubicin treatments. Our results demonstrated that there were no significant differences between doxorubicin and SML +doxorubicin treated mice for their tumor inhibition.