HOME HELP FEEDBACK HOW TO CITE ABSTRACTS ARCHIVE CME INFORMATION SEARCH Cancer Research Clinical Cancer Research Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics Molecular Cancer Research Cancer Prevention Research Cancer Prevention Journals Portal Cancer Reviews Online Annual Meeting Education Book Meeting Abstracts Online		QUICK SEARCH:   [advanced] Author: Keyword(s):

Services Similar articles in this journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Martínez, N. Articles by Piris, M. Search for Related Content PubMed Articles by Martínez, N. Articles by Piris, M.

Preclinical Studies and Early Drug Development: Pharmacology, Pharmacogenetics, and Pharmacogenomics

Transcriptional signature associated with response to Aplidin^® (Plitidepsin) in human T-cell lymphoma cell lines

Spanish National Cancer Ctr., Madrid, Spain and Pharmamar, Madrid, Spain

Abstract

B13

Aplidin^®(Plitidepsin) is a marine compound with antitumoral activity that produces cell cycle G1 arrest, G2 blockage, and apoptosis in different tumor cell types. It was previously described that high concentrations of Plitidepsin (400-500 nM) produced activation of the mitogen activated protein kinases JNK, p38 and ERK; additional studies done at concentrations closer to average IC50 values (i.e. 50 nM) also support the findings of JNK activation. Inhibition of VEGF autocrine loop, reducing VEGF secretion and down-regulation of the VEGFr-1 has also been described. Phase II clinical studies are currently underway in a variety of solid tumors and hematological malignancies.The aim of this study was to investigate the functional changes and molecular signature induced by Plitidepsin in human T cell lymphoma. Therefore, a panel of 5 human T cell lymphoma cell lines was treated with clinically relevant concentrations of Plitidepsin (20 nM). The IC50 of these cell lines are between 10 and 40 nM.Cells were collected at different points of treatment, 0, 6, 24, 48 and 72 hours, for flow cytometry analysis (FACS) and RNA extraction. Cells treated with DMSO were used as controls. Plitidepsin treatment produced apoptosis, measured by Annexin V.To obtain the gene expression signature in response to Plitidepsin in the cell lines studied, a cDNA microarray containing 9300 genes relevant in cancer and drug resistance was used.Genes deregulated at each time-point of treatment in at least 3 of the 5 cell lines were selected. Only those genes whose deregulation was maintained at least in 2 time-points of the treatment were considered. This analysis revealed upregulation of 86 genes and downregulation of 66 genes in response to Plitidepsin. Among the upregulated genes, a group of genes related with apoptosis, such as CASP7, RHOB (Ras homolog gene), BNIP1 (bcl2 interacting protein), CYCS (cytochrome C), the Serine/threonine-protein kinase SGK, and the Mitochondrial ribosomal protein MRPS30, and with signal transduction such as JUN, were found, whereas some genes related with cell cycle check points, such as CDKN2C, CDC45L, CENPF (centromer protein), the cyclins CCNG1, CCNG2 and CCNB2, were downregulated. The heat shock protein HSP70 was also downregulated in response to Plitidepsin treatment. This gene expression signature is comparable to the one previously obtained in B cells (AML and ALL cell lines), although some differences, which can be explained by the different sensibility to Plitidepsin of B or T cells, have been found.