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

  • 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
  • View Affiliations

  • Published online on: October 20, 2014     https://doi.org/10.3892/ijo.2014.2714
  • Pages: 299-307
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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.
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January 2015
Volume 46 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Copy and paste a formatted citation
APA
Liu, Y., Wang, X., Wang, Y., Zhang, Y., Zheng, K., Yan, H. ... Wang, Y. (2015). Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells. International Journal of Oncology, 46, 299-307. https://doi.org/10.3892/ijo.2014.2714
MLA
Liu, Y., Wang, X., Wang, Y., Zhang, Y., Zheng, K., Yan, H., Zhang, L., Chen, W., Wang, X., Liu, Q., Wang, S., Wang, Y."Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells". International Journal of Oncology 46.1 (2015): 299-307.
Chicago
Liu, Y., Wang, X., Wang, Y., Zhang, Y., Zheng, K., Yan, H., Zhang, L., Chen, W., Wang, X., Liu, Q., Wang, S., Wang, Y."Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells". International Journal of Oncology 46, no. 1 (2015): 299-307. https://doi.org/10.3892/ijo.2014.2714