Loading...
Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer by Suppressing the HER2/AKT Signaling Pathway
Zhang W. Bhagwath A.S. Ramzan Z. Williams T.A. Subramaniyan I. Edpuganti V. Kallem R.R. Dunbar K.B. Ding P. Gong K.
Zhang W.
Bhagwath A.S.
Ramzan Z.
Williams T.A.
Subramaniyan I.
Edpuganti V.
Kallem R.R.
Dunbar K.B.
Ding P.
Gong K.
Citations
Altmetric:
Soloist
Composer
Publisher
AACR
Date
2021
Additional date(s)
Abstract
Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro. Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling. ©2021 The Authors; Published by the American Association for Cancer Research
Contents
Subject
epidermal growth factor receptor 2
hydroxyitraconazole
itraconazole
lapatinib
phosphatidylinositol 3 kinase
placebo
protein kinase B
protein S6
small interfering RNA
tyrosine kinase receptor
AKT1 protein, human
cytochrome P450 3A inhibitor
epidermal growth factor receptor 2
ERBB2 protein, human
itraconazole
protein kinase B
adult
aged
Akt signaling
animal experiment
animal model
antineoplastic activity
Article
cancer growth
cancer inhibition
cancer model
cancer patient
cell cycle arrest
cell cycle G1 phase
cell cycle M phase
cell cycle S phase
cell proliferation
clinical article
comparative study
controlled study
down regulation
electrospray
esophageal adenocarcinoma
esophageal squamous cell carcinoma
esophagogastroduodenoscopy
FLO-1 cell line
G1 phase cell cycle checkpoint
gene expression
genetic transcription
human
human cell
in vitro study
KYSE-510 cell line
KYSE-70 cell line
liquid chromatography-mass spectrometry
male
mouse
nonhuman
OE33 cell line
polyacrylamide gel electrophoresis
protein expression
protein phosphorylation
real time polymerase chain reaction
signal transduction
tumor volume
tumor xenograft
ultra performance liquid chromatography
unspecified side effect
animal
apoptosis
Bagg albino mouse
cell cycle
cell motion
clinical trial
drug effect
drug screening
esophageal squamous cell carcinoma
esophagus tumor
female
gene expression regulation
maximum tolerated dose
metabolism
nude mouse
pathology
phase 1 clinical trial
prognosis
tissue distribution
tumor cell culture
Animals
Apoptosis
Cell Cycle
Cell Movement
Cell Proliferation
Cytochrome P-450 CYP3A Inhibitors
Esophageal Neoplasms
Esophageal Squamous Cell Carcinoma
Female
Gene Expression Regulation, Neoplastic
Humans
Itraconazole
Maximum Tolerated Dose
Mice
Mice, Inbred BALB C
Mice, Nude
Prognosis
Proto-Oncogene Proteins c-akt
Receptor, ErbB-2
Tissue Distribution
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
hydroxyitraconazole
itraconazole
lapatinib
phosphatidylinositol 3 kinase
placebo
protein kinase B
protein S6
small interfering RNA
tyrosine kinase receptor
AKT1 protein, human
cytochrome P450 3A inhibitor
epidermal growth factor receptor 2
ERBB2 protein, human
itraconazole
protein kinase B
adult
aged
Akt signaling
animal experiment
animal model
antineoplastic activity
Article
cancer growth
cancer inhibition
cancer model
cancer patient
cell cycle arrest
cell cycle G1 phase
cell cycle M phase
cell cycle S phase
cell proliferation
clinical article
comparative study
controlled study
down regulation
electrospray
esophageal adenocarcinoma
esophageal squamous cell carcinoma
esophagogastroduodenoscopy
FLO-1 cell line
G1 phase cell cycle checkpoint
gene expression
genetic transcription
human
human cell
in vitro study
KYSE-510 cell line
KYSE-70 cell line
liquid chromatography-mass spectrometry
male
mouse
nonhuman
OE33 cell line
polyacrylamide gel electrophoresis
protein expression
protein phosphorylation
real time polymerase chain reaction
signal transduction
tumor volume
tumor xenograft
ultra performance liquid chromatography
unspecified side effect
animal
apoptosis
Bagg albino mouse
cell cycle
cell motion
clinical trial
drug effect
drug screening
esophageal squamous cell carcinoma
esophagus tumor
female
gene expression regulation
maximum tolerated dose
metabolism
nude mouse
pathology
phase 1 clinical trial
prognosis
tissue distribution
tumor cell culture
Animals
Apoptosis
Cell Cycle
Cell Movement
Cell Proliferation
Cytochrome P-450 CYP3A Inhibitors
Esophageal Neoplasms
Esophageal Squamous Cell Carcinoma
Female
Gene Expression Regulation, Neoplastic
Humans
Itraconazole
Maximum Tolerated Dose
Mice
Mice, Inbred BALB C
Mice, Nude
Prognosis
Proto-Oncogene Proteins c-akt
Receptor, ErbB-2
Tissue Distribution
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Subject(s)
Research Projects
Organizational Units
Journal Issue
Genre
Description
Format
Department
Burnett School of Medicine