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Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2009 Aug; Vol. 11 (8), pp. 720-31. - Publication Year :
- 2009
-
Abstract
- The Raf/MEK/ERK pathway is an important mediator of tumor cell proliferation and angiogenesis. Here, we investigated the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells. PD0325901 effects were determined in a panel of melanoma cell lines with different genetic aberrations. PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type melanoma cell lines, with IC(50) in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G(1)-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (cyclin D1, c-Myc, and p27(KIP1)) and apoptosis (Bcl-2 and survivin) regulators were modulated by PD0325901 at the protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally, PD0325901 inhibited the production of the proangiogenic factors vascular endothelial growth factor and interleukin 8 at a transcriptional level. In conclusion, PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing malignant melanoma.
- Subjects :
- Animals
Apoptosis drug effects
Blotting, Western
Cell Line, Tumor
Cell Proliferation drug effects
Diphenylamine pharmacology
Electrophoretic Mobility Shift Assay
Enzyme Inhibitors pharmacology
Female
Gene Expression drug effects
Humans
MAP Kinase Kinase Kinases antagonists & inhibitors
MAP Kinase Kinase Kinases drug effects
Mice
Mice, Nude
Mutation
Oligonucleotide Array Sequence Analysis
Phosphorylation drug effects
Signal Transduction drug effects
Xenograft Model Antitumor Assays
Angiogenesis Inhibitors pharmacology
Antineoplastic Agents pharmacology
Benzamides pharmacology
Diphenylamine analogs & derivatives
Melanoma genetics
Melanoma metabolism
Proto-Oncogene Proteins B-raf genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 11
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 19649202
- Full Text :
- https://doi.org/10.1593/neo.09398