Abstract | BACKGROUND: METHODS: The Transwell assay, Wound-healing assay and Adhesion assay were used to evaluate the inhibition of combined therapy of J-4 and Celecoxib on melanoma cells invasion, migration and adhesion in vitro, respectively. The impaired actin polymerization was observed by confocal microscope and inactivated signal pathways about PKCζ and COX-2 were confirmed by the Western blotting assay. The B16-F10/C57BL mouse melanoma model was used to test the inhibition of combined therapy of J-4 and Celecoxib on melanoma metastasis in vivo. RESULTS: The in vitro results showed that the combination of J-4 and Celecoxib exerted synergistic inhibitory effects on the migration, invasion and adhesion of melanoma B16-F10 and A375 cells with combination index less than 1. The actin polymerization and phosphorylation of Cofilin required in cell migration were severely impaired, which is due to the inactivation of PKCζ related signal pathways and the decrease of COX-2. The combined inhibition of PKCζ and COX-2 induced Mesenchymal-Epithelial Transition (MET) in melanoma cells with the expression of E-Cadherin increasing and Vimentin decreasing. The secretion of MMP-2/ MMP-9 also significantly decreased after the combination treatment. In C57BL/6 mice intravenously injected with B16-F10 cells (5 × 104 cells/mouse), co-treatment of J-4 and Celecoxib also severely suppressed melanoma lung metastasis. The body weight monitoring and HE staining results indicated the low toxicity of the combination therapy. CONCLUSIONS:
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Authors | Ping Zhou, Jiaqi Qin, Yuan Li, Guoxia Li, Yinsong Wang, Ning Zhang, Peng Chen, Chunyu Li |
Journal | Journal of experimental & clinical cancer research : CR
(J Exp Clin Cancer Res)
Vol. 36
Issue 1
Pg. 115
(09 02 2017)
ISSN: 1756-9966 [Electronic] England |
PMID | 28865485
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amidines
- Benzene Derivatives
- Cdh1 Proteins
- Cyclooxygenase 2 Inhibitors
- Fzr1 protein, mouse
- J-4 compound
- Ptgs2 protein, mouse
- Cyclooxygenase 2
- protein kinase C zeta
- Protein Kinase C
- Matrix Metalloproteinase 2
- Matrix Metalloproteinase 9
- Celecoxib
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Topics |
- Amidines
(administration & dosage)
- Animals
- Benzene Derivatives
(administration & dosage)
- Cdh1 Proteins
(genetics)
- Celecoxib
(administration & dosage)
- Cyclooxygenase 2
(genetics)
- Cyclooxygenase 2 Inhibitors
(administration & dosage)
- Epithelial-Mesenchymal Transition
(drug effects)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Matrix Metalloproteinase 2
(genetics)
- Matrix Metalloproteinase 9
(genetics)
- Melanoma, Experimental
(drug therapy, genetics, pathology)
- Mice
- Neoplasm Metastasis
- Protein Kinase C
(antagonists & inhibitors, genetics)
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