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.
Department of Pharmacy, Center for Drug Research, University of Munich, Munich, Germany.
L
L
Schyschka
A
A
Rudy
I
I
Jeremias
N
N
Barth
G R
GR
Pettit
A M
AM
Vollmar
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