A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation

Abstract

BackgroundNasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1.ResultsOur results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts.ConclusionAT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC.

Drugging the HDAC6–HSP90 interplay in malignant cells

“…Likewise, LBH589 activates ERK to disrupt a phosphatase PP1a-HDAC6 complex, and accelerates the turnover of HDAC6 in prostate cancer cells [61]. In addition, HDAC6 is lost upon inhibition of HSP90 in EpsteinBarr virus-positive nasopharyngeal carcinoma cells [62].…”

Heat Shock Protein 90 Is a Potential Therapeutic Target in Cholangiocarcinoma

“…AT13387, a nonansamycin HSP90 inhibitor provided by Astex Pharmaceuticals, was reported to suppress cell growth of various cancer types (non-small-cell lung carcinoma, and nasopharyngeal carcinoma) by previous reports (28,29). No previous study reported, the effectiveness of AT13387 for cholangiocarcinoma cell lines; however, Shapiro and colleagues reported a phase I study of AT13387 for solid tumors, including one cholangiocarcinoma patient.…”

Elemental bioimaging of platinum in mouse tissues by laser ablation-inductively coupled plasma-mass spectrometry for the study of localization behavior of structurally similar complexes

“…Log P values of the two synthesized complexes were calculated using the ChemDraw Ultra 8.0 (CambridgeSoft Coporation, MA, USA). tivated in M199 medium supplemented with 20 g/ml ECGS, 90 g/ml heparin, 20% heat-inactivated fetal bovine serum and 1% P/S [26][27][28]. Cell viability was measured by MTT assay to evaluate the cytotoxicity of the complexes.…”