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Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer
- Source :
- Cancer Letters. 368:46-53
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- The MAP kinase and NF-κB signaling pathways play an important role in thyroid cancer tumorigenesis. We aimed to examine the therapeutic potential of dually targeting the two pathways using AZD6244 and Bortezomib in combination. We evaluated their effects on cell proliferation, cell-cycle progression, apoptosis, cell migration assay, and the activation of the MAPK pathway in vitro and the in vivo using tumor size and immunohistochemical changes of Ki67 and ppRB. We found inhibition of cell growth rate by 10%, 20%, and 56% (p < 0.05), migration to 55%, 61%, and 29% (p < 0.05), and induction of apoptosis to 10%, 15%, and 38% (p < 0.05) with AZD6244, Bortezomib, or combination, respectively. Induction of cell cycle arrest occurred only with drug combination. Dual drug treatment in the xenograft model caused a 94% reduction in tumor size (p < 0.05) versus 15% with AZD6244 and 34% with Bortezomib (p < 0.05) and also reduced proliferative marker Ki67, and increased pRb dephosphorylation. Our results demonstrate a robust therapeutic potential of combining AZD6244 and Bortezomib as an effective strategy to overcome drug resistance encountered in monotherapy in the treatment of thyroid cancer, strongly supporting clinical trials to further test this strategy.
- Subjects :
- Male
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway
Cancer Research
Time Factors
Cell cycle checkpoint
Mice, Nude
Apoptosis
Pharmacology
medicine.disease_cause
Article
Bortezomib
Cell Movement
In vivo
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Neoplasm Invasiveness
Thyroid Neoplasms
Thyroid cancer
Cell Proliferation
Mice, Inbred BALB C
Dose-Response Relationship, Drug
Cell growth
business.industry
Cell Cycle
NF-kappa B
medicine.disease
Xenograft Model Antitumor Assays
Tumor Burden
Oncology
Mutation
Benzimidazoles
Mitogen-Activated Protein Kinases
Carcinogenesis
business
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 03043835
- Volume :
- 368
- Database :
- OpenAIRE
- Journal :
- Cancer Letters
- Accession number :
- edsair.doi.dedup.....58319383fbda717ae993d403bb1593b1