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.
Subject(s)
Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Gene Expression Regulation, Neoplastic/drug effects , Itraconazole/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Animals , Apoptosis , Cell Cycle , Cell Movement , Cell Proliferation , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Squamous Cell Carcinoma/pathology , Female , Humans , Itraconazole/pharmacokinetics , Maximum Tolerated Dose , Mice , Mice, Inbred BALB C , Mice, Nude , Prognosis , Tissue Distribution , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Isolation of putative cancer stem cells (CSCs) in various tumors has generated much excitement among researchers who consider these cells the potential "culprits" behind resistance to conventional therapy. Both cancer and cardiovascular disease are believed to be stem cell disorders involving circulating endothelial progenitors (CEPs) and mesenchymal stem cells (MSCs). CD133 and CD44, markers of CSCs in many tumors, also enrich CEPs and MSCs, respectively. We propose an integrated tumorigenesis model that involves all three interdependent stem cell (CSC, CEP, MSC) compartments by revisiting the "seed and soil" model. Developing therapeutics that can effectively target CSCs and spare normal cardiovascular tissue will remain a challenge. Preliminary laboratory and clinical data on monitoring and targeting colon CSCs, using such a modeling system, are discussed.