1. ¹Department of Pharmacy, Center for Drug Research, University of Munich, Munich, Germany
2. ²Department of Gene Vectors, GSF-Haematologikum, Munich, Germany
3. ³Department of Chemistry, Arizona State University, Tempe, AZ, USA

Correspondence: Dr AM Vollmar, Department of Pharmacy, Center for Drug Research, Butenandtstrae 5-13, D-81377 Munich, Germany. E-mail: Angelika.Vollmar@cup.uni-muenchen.de

⁴These authors contributed equally to this work.

Received 3 August 2007; Revised 6 May 2008; Accepted 15 May 2008; Published online 12 June 2008.

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.