Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer

Koji Tsumagari; Zakaria Y Abd Elmageed; Andrew B Sholl; Paul Friedlander; Mohamed Abdraboh; Mingzhao Xing; A Hamid Boulares; Emad Kandil

doi:10.1016/j.canlet.2015.07.011

Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer

Cancer Lett. 2015 Nov 1;368(1):46-53. doi: 10.1016/j.canlet.2015.07.011. Epub 2015 Jul 21.

Authors

Koji Tsumagari¹, Zakaria Y Abd Elmageed¹, Andrew B Sholl², Paul Friedlander³, Mohamed Abdraboh⁴, Mingzhao Xing⁵, A Hamid Boulares⁶, Emad Kandil⁷

Affiliations

¹ Departments of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
² Departments of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
³ Departments of Otolaryngology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
⁴ Departments of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA.
⁵ Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ The Stanley Scott Cancer Center, Department of Pharmacology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
⁷ Departments of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: ekandil@tulane.edu.

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.

Keywords: AZD6244; Bortezomib; MAPK; NF-κB; Thyroid cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Benzimidazoles / administration & dosage
Bortezomib / administration & dosage
Cell Cycle / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Humans
Male
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Mitogen-Activated Protein Kinases / metabolism
Mutation
NF-kappa B / antagonists & inhibitors*
NF-kappa B / metabolism
Neoplasm Invasiveness
Proto-Oncogene Proteins B-raf / genetics
Signal Transduction / drug effects*
Thyroid Neoplasms / drug therapy*
Thyroid Neoplasms / enzymology
Thyroid Neoplasms / genetics
Thyroid Neoplasms / pathology
Time Factors
Tumor Burden
Xenograft Model Antitumor Assays

Substances

AZD 6244
Benzimidazoles
NF-kappa B
Bortezomib
BRAF protein, human
Proto-Oncogene Proteins B-raf
Mitogen-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding