Abstract
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.
Highlights
Plitidepsin (Aplidin®, APL) is a marine cyclic depsipeptide originally isolated from the tunicateAplidium albicans and currently obtained by synthesis
Given the advanced clinical development of plitidepsin in multiple myeloma and leukemia, we have evaluated the effect of plitidepsin on the viability and the level of Jun N-terminal kinase (JNK) phosphorylation in a panel of these different cancer cell types
Activation in human hematological cancer cells. (A) Multiple myeloma NCI-H929, RPMI8226 and U266B1 cells, and leukemic K562 cells were incubated in the presence of the indicated concentrations of plitidepsin (APL) for 24 h and cell viability was determined by the MTT assay
Summary
Plitidepsin (Aplidin®, APL) is a marine cyclic depsipeptide originally isolated from the tunicateAplidium albicans and currently obtained by synthesis. Plitidepsin has demonstrated strong anticancer activity in a large variety of human cancer cell lines in vitro and in xenografted mice [1]. In cultured cells from solid tumors, plitidepsin induces dose-dependent cell cycle arrest or an acute apoptotic process due primarily to the sustained activation of c-Jun N-terminal kinase (JNK) as revealed by an increased level of phosphorylation [2,3]. Plitidepsin induces several early response genes such as c-JUN, JUNB, JUND, c-FOS, FOSB and FRA1, as well as RELA/p65, the major component of the nuclear transcription factor kappa B (NFkB), while decreasing the cellular content of the c-MYC protein [6]. Plitidepsin increases the cellular content of the p27KIP1 cell cycle inhibitor [10]
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