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oai:repisalud.isciii.es:20.500.12105/70562024-10-07T10:52:11Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19608

00925njm 22002777a 4500 dc Muñoz-Alonso, María J author Álvarez, Enrique author Guillén-Navarro, María José author Pollan-Santamaria, Marina author Avilés, Pablo author Galmarini, Carlos M author Muñoz, Alberto author 2013-05-21 Plitidepsin 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. Mar Drugs. 2013; 11(5): 1677–1692. 10.3390/md11051677 1660-3397 Marine drugs 23697951 http://hdl.handle.net/20.500.12105/7056 Plitidepsin Aplidin JNK Biomarker Xenograft c-Jun N-terminal kinase phosphorylation is a biomarker of plitidepsin activity