Abstract | BACKGROUND: METHODS: The therapeutic effect of PD98059, a MAPK/ERK pathway inhibitor, was examined with respect to cell death, survival, and anti-apoptotic protein expression by means of flow cytometry and immunoblotting in vitro. Additionally, we transplanted green fluorescent protein and luciferase-tagged 143B osteosarcoma cells into the proximal part of the tibia of nude mice. Mice were randomly assigned to treatment with doxorubicin, PD98059, or both. Vehicle-treated mice served as controls. Treatment outcome was assessed by measuring bioluminescence and by monitoring survival. RESULTS: In vitro, ERK1/2 blockage increased the expression of pro-apoptotic proteins and increased cell death in 143B osteosarcoma cells. Doxorubicin treatment increased the expression of Bcl-2, an anti-apoptotic protein, but this upregulation was blocked by combined treatment with PD98059, suggesting a role for ERK1/2 in conferring drug resistance. In osteosarcoma-bearing mice, targeting ERK1/2 with PD98059 resulted in prolonged survival in comparison with vehicle-treated control mice (median survival time, sixty-seven days compared with seventy-four days; p = 0.0272; survival ratio = 0.9122; 95% confidence interval = 0.4354 to 1.389). Standalone doxorubicin treatment yielded similar animal morbidity (median survival time, sixty-seven days compared with seventy-six days; p = 0.0170; survival ratio = 0.8882; 95% confidence interval = 0.4181 to 1.358). Combined PD98059 and doxorubicin treatment further prolonged survival (median survival time, sixty-seven days compared with eighty-two days; p = 0.0023; survival ratio = 0.8232; 95% confidence interval = 0.3606 to 1.286). CONCLUSIONS: Inhibiting ERK1/2 signaling resulted in osteosarcoma cell death by upregulating pro-apoptotic genes and inhibiting the Bcl-2-mediated resistance to doxorubicin. In osteosarcoma-bearing mice, ERK1/2 targeting alone or in combination with doxorubicin prolonged survival as compared with untreated mice.
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Authors | Kyucheol Noh, Kyung-Ok Kim, Neel R Patel, J Robert Staples, Hiroshi Minematsu, Kumar Nair, Francis Young-In Lee |
Journal | The Journal of bone and joint surgery. American volume
(J Bone Joint Surg Am)
Vol. 93
Issue 8
Pg. 723-32
(Apr 20 2011)
ISSN: 1535-1386 [Electronic] United States |
PMID | 21508279
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Flavonoids
- Doxorubicin
- Luciferases
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Topics |
- Animals
- Apoptosis
(drug effects)
- Bone Neoplasms
(drug therapy, enzymology)
- Cell Death
(drug effects)
- Cell Survival
(drug effects)
- Doxorubicin
(pharmacology)
- Flavonoids
(pharmacology)
- Flow Cytometry
- Inflammation
(drug therapy, enzymology)
- Luciferases
- Mice
- Mitogen-Activated Protein Kinase 1
(antagonists & inhibitors)
- Mitogen-Activated Protein Kinase 3
(antagonists & inhibitors)
- Osteosarcoma
(drug therapy, enzymology)
- Random Allocation
- Signal Transduction
- Tumor Cells, Cultured
- Up-Regulation
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