Abstract |
Notch-stimulated signaling cascade results in transcriptional regulation of genes involved in cell fate decision, apoptosis and proliferation and has been implicated in various malignancies. Here, we investigated the impact of MRK003, an inhibitor of this pathway, on myeloma and lymphoma cells. We first studied the expression patterns of notch receptors and ligands on multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Next, we used a γ- secretase inhibitor, MRK003 to test the importance of notch-stimulated pathways in MM and NHL disease biology. We observed expression of notch receptors and ligands on MM and NHL cell lines. MRK003 treatment induced caspase-dependent apoptosis and inhibited proliferation of MM and NHL cell lines and patient cells. Examination of signaling events after treatment showed time-dependent decrease in levels of the notch intracellular domain, Hes1 and c-Myc. MRK003 downregulated cyclin D1, Bcl-Xl and Xiap levels in NHL cells and p21, Bcl-2 and Bcl-Xl in MM cells. In addition, MRK003 caused an upregulation of pAkt, indicating crosstalk with the PI3K/Akt pathway. We evaluated MRK003 in combination with Akt1/2 kinase inhibitor and observed synergy in killing MM and NHL cell lines examined.
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Authors | V Ramakrishnan, S Ansell, J Haug, D Grote, T Kimlinger, M Stenson, M Timm, L Wellik, T Halling, S V Rajkumar, S Kumar |
Journal | Leukemia
(Leukemia)
Vol. 26
Issue 2
Pg. 340-8
(Feb 2012)
ISSN: 1476-5551 [Electronic] England |
PMID | 21826062
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cyclic S-Oxides
- DNA Primers
- Enzyme Inhibitors
- MRK 003
- Thiadiazoles
- Amyloid Precursor Protein Secretases
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Topics |
- Amyloid Precursor Protein Secretases
(antagonists & inhibitors)
- Apoptosis
(drug effects)
- Base Sequence
- Cell Line, Tumor
- Cyclic S-Oxides
(pharmacology, therapeutic use)
- DNA Primers
- Drug Screening Assays, Antitumor
- Enzyme Inhibitors
(pharmacology, therapeutic use)
- Humans
- Lymphoma, Non-Hodgkin
(drug therapy, pathology)
- Multiple Myeloma
(drug therapy, pathology)
- Reverse Transcriptase Polymerase Chain Reaction
- Thiadiazoles
(pharmacology, therapeutic use)
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