Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway

Abstract

Itraconazole, an FDA-approved antifungal, has anti-tumor 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 OE33derived 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 esophageal cancer patients, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent anti-tumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.

Human umbilical cord mesenchymal stem cells: Heralding an effective treatment against esophageal cancer?

“…From a genetic viewpoint, cyclin D1, p53, p16INK4a, p14ARF, epidermal growth factor receptors, retinoic acid, COX‐2, fragile histidine triad, and retinoic acid receptor beta 2 have been shown to play a role in ESCC (Hochwald & Kukar, 2014). The involvement of some signaling pathways has been approved in EC, for example, PI3K/AKT/mTOR, NF‐κB, Wnt/β‐catenin, Ezh2‐Notch1, and HER2/Akt signaling pathways (M. Chen et al, 2018; B. Li et al, 2009; Shi et al, 2019; Q. Wang et al, 2019; Zhang et al, 2021). In terms of genomic amplifications, VEGFA , ERBB2 , GATA6 , and GATA4 are more amplified in EAC, while SOX2 , CCND1 , and TP63 are commonly amplified in ESCC (Baba et al, 2017).…”

“…for example, PI3K/AKT/mTOR, NF-κB, Wnt/β-catenin, Ezh2-Notch1, and HER2/Akt signaling pathways (M. Chen et al, 2018;B. Li et al, 2009;Shi et al, 2019;Zhang et al, 2021).…”

MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen

“…Itraconazole is a generic broad-spectrum antifungal drug that is also seeing a renaissance in anticancer applications [184][185][186][187][188][189]. It has three attributes that recommend its use during cancer treatment: (1) it inhibits Hedgehog (Hh) signaling [189][190][191][192][193], (2) it inhibits 5-lipoxygenase (5-LO) [193][194][195][196], and (3) it inhibits the P-gp efflux pump [188,[197][198][199].…”

The roles and mechanisms of the lncRNA-miRNA axis in the progression of esophageal cancer: a narrative review

“…HER2 is a member of the EGFR family and a tyrosine kinase, which is involved in a variety of biological progress of tumor cells. The experiment shows that HER2/neu is highly expressed in esophageal cancer, and itraconazole ( 21 ) and trastuzumab ( 22 ) are its main targeted drugs. VEGFs play an important role in inducing the proliferation of vascular endothelial cells and the formation of new blood vessels.…”