Abstract
The purpose of this study was the use of rhodamine 123 (Rho123) accumulation in peripheral blood CD8+cells as a surrogate indicator to evaluate the modulating effect of P-glycoprotein (P-gp) inhibitors in the multidrug resistance (MDR) tumor-bearing mouse model. Rho123 was administered to mice, and the fluorescence level in CD8+ cells was measured. Cepharanthine hydrochloride (CH) and verapamil (VER), two P-gp inhibitors, were administered to mice 1 hour prior to Rho123 administration in vivo or added to peripheral blood 1 hour prior to Rho123 addition ex vivo. The tumor inhibition effect of 5-fluorouracil/adriamycin/cisplatin (FAP) protocol plus CH was also investigated. A concentration- or dose-response relationship was shown between the concentration and dose of CH and Rho123 accumulation or the antitumor activity. In conclusion, the measurement of Rho123 accumulation in CD8+ cells provides a surrogate assay for the screening of candidate P-gp inhibitors in preclinical trials, and CH is effective in modulating P-gp-mediated MDR in vivo.
Highlights
Multidrug resistance (MDR) remains the major obstacle to success in a wide variety of advanced malignancies, in solid cancers
The purpose of this study was the use of rhodamine 123 (Rho123) accumulation in peripheral blood CD8+cells as a surrogate indicator to evaluate the modulating effect of P-glycoprotein (P-gp) inhibitors in the multidrug resistance (MDR) tumor-bearing mouse model
The measurement of Rho123 accumulation in CD8+ cells provides a surrogate assay for the screening of candidate P-gp inhibitors in preclinical trials, and Cepharanthine hydrochloride (CH) is effective in modulating P-gp-mediated MDR in vivo
Summary
Multidrug resistance (MDR) remains the major obstacle to success in a wide variety of advanced malignancies, in solid cancers. One of the best methods of reversing MDR and increasing the efficacy of anticancer drugs is to use the potent P-gp inhibitors modulating P-gp function and/or expression. It is an important step to use assays to evaluate the effect of candidate drugs as inhibitors of P-gp function in vivo after the drugs were found to have an MDR-reversing effect in vitro. The P-gp in the lymphocytes appears functionally identical to that observed in multidrug resistant cells; they have the same substrate and antagonist specificities [5, 7, 8]. Since the expression and function of P-gp in CD56+ cells are the highest, is Rho123 accumulation widely used in CD56+ populations as Journal of Biomedicine and Biotechnology
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