Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells.

Abstract

The low efficacy of single-drug chemotherapy forms the basis for combination therapy in esophageal squamous cell carcinoma. SNX-2112, a selective heat shock protein 90 (Hsp90) inhibitor, was recently reported as being effective in combination with cisplatin and paclitaxel. In this study, we investigated the effect of SNX-2112 in combination with 5-fluorouracil (5-FU), another first-line anticancer drug, in esophageal cancer. Unexpectedly, tetrazolium assay revealed that the combination of SNX-2112 with 5-FU exhibited antagonistic effect. Flow cytometry revealed that the SNX-2112 and 5-FU combination greatly decreased the number of G2/M cells compared to SNX-2112-only treatment in Eca‑109 cells. This effect might be related to the altered mRNA level of cyclin-related genes including cyclin D1, Chk2 and Cdk4. Further, 5-FU attenuated SNX-2112-induced apoptosis by decreasing poly(ADP-ribose) polymerase (PARP) cleavage and inactivating caspase-3, -8 and -9. Additionally, 5-FU suppressed the SNX-2112-induced decrease of mitochondrial membrane potential. Moreover, 5-FU partly recovered Hsp90 client proteins, including Akt, p-Akt, inhibitor of κB kinase (IKK)α, extracellular signal-regulated kinase (ERK)1/2, and glycogen synthase kinase (GSK)-3β, which SNX-2112 had downregulated. Taken together, this is the first report that the combination of SNX-2112 with 5-FU exhibited antagonistic effect in esophageal cancer cells by affecting growth inhibition, cell cycle, apoptosis, and Hsp90 client proteins, suggesting that care is required in the clinical application of combined SNX-2112 and 5-FU.

• Authors: Yuting Liu, Xiao Wang, Ying Wang, Yi Zhang, Kai Zheng, Haizhao Yan, Li Zhang, Wenbo Chen, Xiaoyan Wang, Qiuying Liu, Shaoxiang Wang, Yifei Wang
• Journal: International journal of oncology (Int J Oncol) Vol. 46 Issue 1 Pg. 299-307 (Jan 2015) ISSN: 1791-2423 [Electronic] Greece
• PMID: 25333998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HSP90 Heat-Shock Proteins
• Heterocyclic Compounds, 4 or More Rings
• SNX 2112
• Matrix Metalloproteinases
• Fluorouracil

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Squamous Cell (drug therapy, pathology)
• Drug Antagonism
• Esophageal Neoplasms (drug therapy, pathology)
• Esophageal Squamous Cell Carcinoma
• Fluorouracil (administration & dosage, pharmacology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• HSP90 Heat-Shock Proteins (metabolism)
• Heterocyclic Compounds, 4 or More Rings (administration & dosage, pharmacology)
• Humans
• Matrix Metalloproteinases (metabolism)
• Tumor Cells, Cultured