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Article

Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress

  • Authors:
    • Takako Asano
    • Akinori Sato
    • Makoto Isono
    • Kazuki Okubo
    • Keiichi Ito
    • Tomohiko Asano
  • View Affiliations / Copyright

    Affiliations: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359‑8513, Japan
  • Pages: 797-801
    |
    Published online on: September 29, 2015
       https://doi.org/10.3892/br.2015.523
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Abstract

There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress has recently emerged as a new approach in the treatment of malignancies. In the present study, we hypothesized that the histone deacetylase inhibitor belinostat would increase the amount of unfolded proteins in cells by inhibiting heat‑shock protein (HSP) 90, and that the proteasome inhibitor bortezomib would inhibit their degradation by inhibiting the proteasome, thus causing ubiquitinated protein accumulation and ER stress synergistically. The combination of bortezomib and belinostat induced significant increases in apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). The combination also suppressed colony formation significantly (P<0.05). As co‑treatment with the pan‑caspase inhibitor Z‑VAD‑FMK changed the number of Annexin V‑positive cells, this combination‑induced apoptosis was considered caspase dependent. Mechanistically, the combination synergistically caused ubiquitinated proteins to accumulate and induced ER stress, as evidenced by the increased expression of glucose‑regulated protein 78 and HSP70. To the best of our knowledge, this is the first study demonstrating the beneficial combined effect of bortezomib and belinostat in renal cancer cells. The study provides a basis for clinical studies with the combination in patients with advanced renal cancer.
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Copy and paste a formatted citation
Spandidos Publications style
Asano T, Sato A, Isono M, Okubo K, Ito K and Asano T: Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress. Biomed Rep 3: 797-801, 2015.
APA
Asano, T., Sato, A., Isono, M., Okubo, K., Ito, K., & Asano, T. (2015). Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress. Biomedical Reports, 3, 797-801. https://doi.org/10.3892/br.2015.523
MLA
Asano, T., Sato, A., Isono, M., Okubo, K., Ito, K., Asano, T."Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress". Biomedical Reports 3.6 (2015): 797-801.
Chicago
Asano, T., Sato, A., Isono, M., Okubo, K., Ito, K., Asano, T."Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress". Biomedical Reports 3, no. 6 (2015): 797-801. https://doi.org/10.3892/br.2015.523
Copy and paste a formatted citation
x
Spandidos Publications style
Asano T, Sato A, Isono M, Okubo K, Ito K and Asano T: Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress. Biomed Rep 3: 797-801, 2015.
APA
Asano, T., Sato, A., Isono, M., Okubo, K., Ito, K., & Asano, T. (2015). Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress. Biomedical Reports, 3, 797-801. https://doi.org/10.3892/br.2015.523
MLA
Asano, T., Sato, A., Isono, M., Okubo, K., Ito, K., Asano, T."Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress". Biomedical Reports 3.6 (2015): 797-801.
Chicago
Asano, T., Sato, A., Isono, M., Okubo, K., Ito, K., Asano, T."Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress". Biomedical Reports 3, no. 6 (2015): 797-801. https://doi.org/10.3892/br.2015.523
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