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Title

c-Jun N-terminal kinase phosphorylation is a biomarker of plitidepsin activity

AuthorsMuñoz-Alonso, María J. ; Muñoz Terol, Alberto
Issue Date2013
PublisherMultidisciplinary Digital Publishing Institute
CitationMarine Drugs 11(5): 1677-1692 (2013)
AbstractPlitidepsin is an antitumor drug of marine origin currently in Phase III clinical trials in multiple myeloma. In cultured cells, plitidepsin induces cell cycle arrest or an acute apoptotic process in which sustained activation of c-Jun N-terminal kinase (JNK) plays a crucial role. With a view to optimizing clinical use of plitidepsin, we have therefore evaluated the possibility of using JNK activation as an in vivo biomarker of response. In this study, we show that administration of a single plitidepsin dose to mice xenografted with human cancer cells does indeed lead to increased phosphorylation of JNK in tumors at 4 to 12 h. By contrast, no changes were found in other in vitro plitidepsin targets such as the levels of phosphorylated-ERK, -p38MAPK or the protein p27KIP1. Interestingly, plitidepsin also increased JNK phosphorylation in spleens from xenografted mice showing similar kinetics to those seen in tumors, thereby suggesting that normal tissues might be useful for predicting drug activity. Furthermore, plitidepsin administration to rats at plasma concentrations comparable to those achievable in patients also increased JNK phosphorylation in peripheral mononuclear blood cells. These findings suggest that changes in JNK activity provide a reliable biomarker for plitidepsin activity and this could be useful for designing clinical trials and maximizing the efficacy of plitidepsin.
DescriptionThis is an open access article distributed under the Creative Commons Attribution License.-- et al.
Publisher version (URL)http://dx.doi.org/10.3390/md11051677
URIhttp://hdl.handle.net/10261/123847
DOI10.3390/md11051677
Identifiersdoi: 10.3390/md11051677
issn: 1660-3397
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