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 topoisomerase I camptothecin and the inhibitor of 26S proteasome MG132. The combination of sodium butyrate and camptothecin resulted in a strong synergistic cytotoxicity, as revealed by combination indices of 0.77 and 0.52 calculated at IC(50) and IC(75). Synergistic interactions were also demonstrated for combinations of sodium butyrate and MG132, camptothecin and MG132 and for a combination of all three compounds. The cytotoxic effects observed after the combined treatments can be considered a consequence of apoptosis, as suggested by the appearance of morphological signals of apoptosis and by the activation 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 p53, E2F-1 and Bcl-2. The addition of MG132 to sodium butyrate counteracted the effect on p53 only, while the addition of camptothecin to sodium butyrate 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 effects exerted on the levels of these regulatory proteins can explain the synergistic interactions demonstrated between sodium butyrate, camptothecin and MG132.
Lauricella
M
M
Department of Cellular and Developmental Biology, Biochemistry Section, University of Palermo, Italy.
Calvaruso
G
G
Giuliano
M
M
Carabillò
M
M
Emanuele
S
S
Vento
R
R
Tesoriere
G
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D002166:Camptothecin / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007976:Leupeptins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012175:Retinoblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D002087:Butyrates; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D007976:Leupeptins; D019253:Proto-Oncogene Proteins c-bcl-2; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D002166:Camptothecin