Increase of Sensitivity and Uptake of Vinblastine by Reserpine in Rat Ascites Hepatoma

Abstract

We investigated the effect of reserpine on the antitumor effect of vinblastine (VBL) with regard to the drug resistance of rat ascites hepatomas. The sensitivity to VBL was in the order of AH13>AH44>AH109A>AH66 cells in the in vitro growth-inhibitory test, and AH66 cells were inherently most resistant to VBL. The intracellular accumulation of VBL was lower in resistant cells than in sensitive cells. Reserpine increased the sensitivity to VBL in the order of AH66>AH109A>AH44>AH13 cells. The antitumor synergism was also observed in the in vivo experiments using AH44 and AH66. Reserpine enhanced the VBL accumulation more than 2 times in AH66 and AH109A cells, but slightly increased it in AH13 and AH44 cells. These results indicated that the synergistic effect of reserpine was more potent in relatively resistant cell lines to VBL, and the effect was caused by the enhancement of VBL accumulation. On the other hand, the enhanced growth-inhibitory effect and the accumulation of VBL in the presence of reserpine were not influenced by further preincubation with reserpine. Reserpine also did not influence the intracellular level of VBL increased by 2, 4-dinitrophenol in a glucose deprived medium. Reserpine decreased the VBL extrusion from AH66 cells more strongly than that from AH44 cells. These results indicated the possibility that reserpine interfered with the VBL efflux process, while it might not influence the VBL influx process. In conclusion, reserpine potentiated the effect of VBL on resistant ascites hepatoma cells more than on sensitive cells, and the synergistic effect of reserpine could be explained by the inhibition of VBL efflux and VBL accumulation in tumor cells.