Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP.
Spongistatin 1 is a new experimental chemotherapeutic agent isolated from marine sponges. Here we show that spongistatin 1 potently induces cell death in patient primary acute leukemic cells with higher efficiency than 8/10 clinically used cytotoxic drugs and prevents long-term survival of leukemic cell lines. Spongistatin 1 triggers caspase-dependent apoptosis in Jurkat T cells by the release of cytochrome c, Smac/DIABLO and Omi/HtrA2. As caspase-9 acts as an initiator caspase and Bcl-2 and Bcl-xL overexpression suppress spongistatin 1-induced apoptosis, cell death is mediated through the mitochondrial apoptosis pathway. Importantly, spongistatin 1 leads to the degradation of the antiapoptotic X-linked inhibitor of apoptosis protein. In apoptosis-resistant leukemic tumor cells overexpressing XIAP, spongistatin 1 effectively causes cell death and potentiates cell death induction by other apoptosis-promoting factors that might be caused by spongistatin 1-mediated degradation of XIAP. Our data show that spongistatin 1 represents a promising novel therapeutic agent for the treatment of leukemic tumor cells especially in the clinically highly relevant situation of chemoresistance due to overexpression of XIAP.
Schyschka
L
L
Department of Pharmacy, Center for Drug Research, University of Munich, Munich, Germany.
Rudy
A
A
Jeremias
I
I
Barth
N
N
Pettit
G R
GR
Vollmar
A M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D024101:Mitochondrial Proteins; D011161:Porifera; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects* / Q000378:metabolism; D000095702:Polyether Toxins
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018942:Macrolides; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C083856:spongistatin 1; D000095702:Polyether Toxins