Suramin inhibits death receptor-induced apoptosis in vitro and fulminant apoptotic liver damage in mice.
Suramin is a polysulfonated derivative of urea and has been widely used both to treat infections and as a chemotherapeutic drug. Suramin has been shown to inhibit growth factor signaling pathways; however, its effect on apoptosis is unknown. Here we show that suramin inhibits apoptosis induced through death receptors in hepatoma and lymphoma cells. It also inhibits the proapoptotic effect of chemotherapeutic drugs. The antiapoptotic mechanism is specific to cell type and is caused by reduced activation, but not altered composition, of the death-inducing signaling complex (DISC), and by inhibition of the initiator caspases 8, 9 and 10. Suramin also shows similar effects in in vivo models: apoptotic liver damage induced by CD95 stimulation and endotoxic shock mediated by tumor-necrosis factor (TNF) are inhibited in mice, but necrotic liver damage is not inhibited in a rat model of liver transplantation. Thus, the antiapoptotic property of suramin in the liver may be therapeutically exploited.
Eichhorst
Sören T
ST
Ludwig-Maximilians-University Munich, University Hospital Grosshadern, Department of Internal Medicine II, Marchioninistrasse 15, D-81377 Munich, Germany.
Krueger
Andreas
A
Müerköster
Susanne
S
Fas
Stefanie C
SC
Golks
Alexander
A
Gruetzner
Uwe
U
Schubert
Louise
L
Opelz
Christine
C
Bilzer
Manfred
M
Gerbes
Alexander L
AL
Krammer
Peter H
PH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D005720:Gamma Rays; D006801:Humans; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D000970:Antineoplastic Agents; D018124:Receptors, Tumor Necrosis Factor; D014344:Trypanocidal Agents; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D013498:Suramin; D003907:Dexamethasone; D020169:Caspases