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.
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Acknowledgements
We thank Dr Krammer and Dr Walczak (German Cancer Research Center, Heidelberg, Germany), Dr Schulze-Osthoff (University of Münster, Germany) as well as Dr Duckett (University of Miami School of Medicine, USA) for supplying the used Jurkat T-cell clones. We thank the Bayrische Forschungsstiftung for financial support (LS).
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Schyschka, L., Rudy, A., Jeremias, I. et al. Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP. Leukemia 22, 1737–1745 (2008). https://doi.org/10.1038/leu.2008.146
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DOI: https://doi.org/10.1038/leu.2008.146