Synergistic cytotoxic interactions between sodium butyrate, MG132 and camptothecin in human retinoblastoma Y79 cells

This paper studies the effects caused in human retinoblastoma Y79 cells by treatment with combinations of sodium butyrate, the inhibitor of topoisomer ase I camptothecin and the inhibitor of 26S proteasome MG132. The combinati on of sodium butyrate and camptothecin resulted in a strong synergistic cyt otoxicity, as revealed by combination indices of 0.77 and 0.52 calculated a t IC50 and IC75 Synergistic interactions were also demonstrated for combina tions of sodium butyrate and MG132, camptothecin and MG132 and for a combin ation of all three compounds. The cytotoxic effects observed after the comb ined treatments can be considered a consequence of apoptosis, as suggested by the appearance of morphological signals of apoptosis and by the activati on of caspase-3 with degradation of poly-ADP ribose polymerase and lamin B. Treatment of Y79 cells with sodium butyrate alone lowered the levels of p5 3, E2F-1 and Bcl-2. The addition of MG132 to sodium butyrate counteracted t he effect on p53 only, while the addition of camptothecin to sodium butyrat e counteracted the effect on both p53 and E2F-1. The treatment of Y79 cells with the triple combination increased the level of p53, decreased that of Bcl-2, while the level of E2F-1 was not modified. We suggest that the effec ts exerted on the levels of these regulatory proteins can explain the syner gistic interactions demonstrated between sodium butyrate, camptothecin and MG132. Copyright (C) 2000 S. Karger AG. Basel.