title: Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer.
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.
authors.affiliation: 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.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsumagari
authors.affiliation: 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.
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.affiliation: Departments of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Sholl
authors.affiliation: Departments of Otolaryngology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Friedlander
authors.affiliation: Departments of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdraboh
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
authors.affiliation: The Stanley Scott Cancer Center, Department of Pharmacology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
authors.affiliation: 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.
authors.forename: Emad
authors.initials: E
authors.lastname: Kandil
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage; D000069286:Bortezomib / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D016328:NF-kappa B; D000069286:Bortezomib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: AZD6244; Bortezomib; MAPK; NF-κB; Thyroid cancer