Spongistatin 1: A new chemosensitizing marine compound that degrades XIAP

L. Schyschka, A. Rudy, I. Jeremias, N. Barth, George Pettit, A. M. Vollmar

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1737-1745
Number of pages9
JournalLeukemia
Volume22
Issue number9
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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