Abstract | BACKGROUND: METHODS: RESULTS:
GSK-3 inhibition reduced both basal and TNF-alpha induced NF-kappaB luciferase activity. Knockdown of GSK-3 beta reduced nuclear factor kappa B luciferase activity to a greater extent than GSK-3 alpha, and the greatest effect was seen with dual knockdown of both GSK-3 isoforms. GSK-3 inhibition also resulted in reduction of the NF-kappaB target proteins XIAP, Bcl-XL, and cyclin D1, associated with growth inhibition and decreased clonogenic survival. In all cell lines, treatment with either AR-A014418, or gemcitabine led to growth inhibition in a dose- and time-dependent manner. However, with the exception of PANC-1 where drug synergy occurred with some dose schedules, the inhibitory effect of combined drug treatment was additive, sub-additive, or even antagonistic. CONCLUSION:
GSK-3 inhibition has anticancer effects against pancreatic cancer cells with a range of genetic backgrounds associated with disruption of NF-kappaB, but does not significantly sensitize these cells to the standard chemotherapy agent gemcitabine. This lack of synergy might be context or cell line dependent, but could also be explained on the basis that although NF-kappaB is an important mediator of pancreatic cancer cell survival, it plays a minor role in gemcitabine resistance. Further work is needed to understand the mechanisms of this effect, including the potential for rational combination of GSK3 inhibitors with other targeted agents for the treatment of pancreatic cancer.
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Authors | Shadi Mamaghani, Satish Patel, David W Hedley |
Journal | BMC cancer
(BMC Cancer)
Vol. 9
Pg. 132
(Apr 30 2009)
ISSN: 1471-2407 [Electronic] England |
PMID | 19405981
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- NF-kappa B
- Protein Kinase Inhibitors
- Tumor Necrosis Factor-alpha
- Deoxycytidine
- Glycogen Synthase Kinase 3
- Gemcitabine
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Topics |
- Antineoplastic Agents
(therapeutic use)
- Cell Line, Tumor
- Deoxycytidine
(analogs & derivatives, therapeutic use)
- Down-Regulation
- Glycogen Synthase Kinase 3
(antagonists & inhibitors, genetics, metabolism)
- Humans
- NF-kappa B
(genetics, metabolism)
- Pancreatic Neoplasms
(drug therapy, enzymology, genetics, metabolism)
- Protein Kinase Inhibitors
(pharmacology)
- Tumor Necrosis Factor-alpha
(genetics, metabolism)
- Gemcitabine
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