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Series GSE5681 Query DataSets for GSE5681
Status Public on Sep 15, 2006
Title Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.

Keywords: Aplidin, araC, drug combination, hematological malignancies
Overall design Overall goal of the experiment was to obtain molecular insight into the mechanism of action of Aplidin alone as well as its combination with AraC.
SKI-DLCL cells were treated in vitro with IC50 doses for Aplidin, AraC or Aplidin+AraC combination. Each samples was done in biological triplicates. Total number of samples was 12.
Alternatively, SKI-DLCL cells were injected into scid mice and when the tumor was pulpable animals were given a single dose of Aplidin 1mg/kg and AraC 50mg/kg in combination. On day eight after drugs administration tumors were harvested and total RNA was isolated. No replicates are available. Data was validated using semi-quantitative RT-PCR
Contributor(s) Humeniuk R, Menon LG, Saydam G, Jimeno J, Bertino JR, Banerjee D, Mishra PJ
Citation(s) 17713546
Submission date Aug 31, 2006
Last update date Dec 06, 2018
Contact name Pravin Mishra
Organization name UMDNJ
Department Pharmacology
Lab Bertino/Banerjee
Street address 195 Little Albany St.
City New Brunswick
State/province NJ
ZIP/Postal code 08904
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (14)
GSM132760 SKI-DLCL_tumor_untreated animals
GSM132916 SKI-DLCL_tumor_animals treated with 1mg/kg Aplidin_50mg/kg AraC
GSM132917 SKI-DLCL cells_untreated_24h_1rpt
BioProject PRJNA96969

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE5681_RAW.tar 45.2 Mb (http)(custom) TAR (of CEL)

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