Rocaglamide and a XIAP inhibitor cooperatively sensitize TRAIL-mediated apoptosis in Hodgkin's lymphomas.

Abstract

Although most of the patients with Hodgkin's lymphoma (HL) can be cured by the current regimen of high-dose multiagent chemotherapy, the treatment causes high risks of later toxicities including secondary malignancies. Therefore, new rational strategies are needed for HL treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent due to its tumor selectivity and its lack of toxicity for normal cells. Unfortunately, many cancers remain resistant to TRAIL including HL. HL is characterized by enhanced expression of cellular caspase-8 (FLICE)-inhibitory protein (c-FLIP) and X-linked inhibitor of apoptosis (XIAP), which block receptor-mediated apoptosis by inhibiting caspase-8 and caspase-3, respectively. We have recently discovered the herbal compound Rocaglamide, which breaks TRAIL-resistance in acute T cell leukemia through inhibition of c-FLIP expression. We have also shown that small molecule XIAP inhibitors can sensitize TRAIL-mediated apoptosis in several resistant tumors. However, whether targeting XIAP or c-FLIP is also a suitable strategy to prime HL cells for TRAIL-induced apoptosis has not yet been investigated. In our study, we show that Rocaglamide suppresses c-FLIP expression in HL cells in a dose- and time-dependent manner. However, downregulation of c-FLIP alone was not sufficient to sensitize TRAIL-induced apoptosis in HL cells. Similarly, treatment of HL cells with a small molecule XIAP inhibitor resulted in a moderate induction of apoptosis. However, inhibition of XIAP alone was also not sufficient to enhance TRAIL-induced cell death. Synergistic increase in TRAIL-mediated killing of HL cells was only obtained by combination of Rocaglamide and XIAP inhibitors. Our study demonstrates that targeting both c-FLIP and XIAP are necessary for an efficient treatment of HL.

• Authors: Marco Giaisi, Rebecca Köhler, Simone Fulda, Peter H Krammer, Min Li-Weber
• Journal: International journal of cancer (Int J Cancer) Vol. 131 Issue 4 Pg. 1003-8 (Aug 15 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 21952919 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Benzofurans
• CASP8 and FADD-Like Apoptosis Regulating Protein
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• rocaglamide

Topics

• Apoptosis (physiology)
• Benzofurans (pharmacology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (physiology)
• Cell Line, Tumor
• Hodgkin Disease (pathology)
• Humans
• TNF-Related Apoptosis-Inducing Ligand (physiology)
• X-Linked Inhibitor of Apoptosis Protein (antagonists & inhibitors)