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| 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
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| 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
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| 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
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| Contributor(s) |
Humeniuk R, Menon LG, Saydam G, Jimeno J, Bertino JR, Banerjee D, Mishra PJ |
| Citation(s) |
17713546 |
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| Submission date |
Aug 31, 2006 |
| Last update date |
Dec 06, 2018 |
| Contact name |
Pravin Mishra |
| E-mail(s) |
mishrapr@umdnj.edu
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| Organization name |
UMDNJ
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| Department |
Pharmacology
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| Lab |
Bertino/Banerjee
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| Street address |
195 Little Albany St.
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| City |
New Brunswick |
| State/province |
NJ |
| ZIP/Postal code |
08904 |
| Country |
USA |
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| Platforms (1) |
| GPL571 |
[HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array |
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| Samples (14)
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| 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 |
| GSM132918 |
SKI-DLCL cells_untreated_24h_2rpt |
| GSM132920 |
SKI-DLCL cells_untreated_24h_rpt3 |
| GSM132941 |
SKI-DLCL cells_Aplidin 3nM_24h_rpt1 |
| GSM132944 |
SKI-DLCL cells_Aplidin 3.0nM_24h_rpt2 |
| GSM132947 |
SKI-DLCL cells_Aplidin treated 3nM_24h_rpt3 |
| GSM132949 |
SKI-DLCL cells_AraC 20nM_24h_rpt1 |
| GSM132950 |
SKI-DLCL cells_AraC 20nM_24h_rpt2 |
| GSM132953 |
SKI-DLCL cells_AraC 20nM_24h_rpt3 |
| GSM132955 |
SKI-DLCL cells_Aplidin 1.5nM AraC 5nM_24h_rpt1 |
| GSM132956 |
SKI-DLCL cells_Aplidin 1.5 nM AraC 5nM_24h_rpt2 |
| GSM132960 |
SKI-DLCL cells_Aplidin 1.5 nM AraC 5.0 nM_24h_rpt3 |
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| Relations |
| BioProject |
PRJNA96969 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE5681_RAW.tar |
45.2 Mb |
(http)(custom) |
TAR (of CEL) |
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