Abstract |
In the current study, we have examined the efficacy of a Src/Abl kinase inhibitor SKI-606 ( Bosutinib) for its effect on prostate cancer growth and skeletal metastasis. Treatment of highly invasive human prostate cancer cells PC-3 and DU-145 with different doses of SKI-606 decreased Src activation, cell proliferation, migration, and invasion as determined by Matrigel Boyden chamber invasion assay. For in vivo studies, PC-3 cells were inoculated through s.c. or i.t. route into male BALB/c nu/nu or Fox Chase severe combined immunodeficient mice, respectively. Experimental animals treated with SKI-606 developed tumors of a significantly smaller volume and a significant decrease (50%) in experimental skeletal lesion area. A marked increase (32%) in bone volume to tumor volume ratio was also seen by micro-computed tomography analysis of tibias from control and experimental groups of animals. Western blot analysis showed the ability of SKI-606 to significantly decrease the phosphorylation of signaling molecules (AKT, mitogen-activated protein kinase, focal adhesion kinase) and the expression of tumor progression-associated genes uPAR, MMP-2, MMP-9, N-cadherin, fibronectin, BMP-2 ( bone morphogenetic protein 2), BMP-6 ( bone morphogenetic protein 6), IL-8 ( interleukin 8), and TGF-beta ( transforming growth factor beta) in prostate cancer cells. SKI-606 is currently in clinical trials for breast cancer and chronic myelogenous leukemia. Results from these studies provide convincing evidence for evaluating its efficacy in prostate cancer patients.
|
Authors | Shafaat A Rabbani, Maria-Luisa Valentino, Ani Arakelian, Suhad Ali, Frank Boschelli |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 9
Issue 5
Pg. 1147-57
(May 2010)
ISSN: 1538-8514 [Electronic] United States |
PMID | 20423991
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Aniline Compounds
- Antineoplastic Agents
- Nitriles
- Quinolines
- bosutinib
|
Topics |
- Aniline Compounds
(pharmacology, therapeutic use)
- Animals
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Bone Neoplasms
(genetics, secondary)
- Carcinoma
(drug therapy, genetics, pathology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Mice, SCID
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Nitriles
(pharmacology, therapeutic use)
- Prostatic Neoplasms
(drug therapy, genetics, pathology)
- Quinolines
(pharmacology, therapeutic use)
- Tumor Burden
(drug effects, genetics)
- Xenograft Model Antitumor Assays
|