title: Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress.
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.
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Asano
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Isono
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Okubo
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Asano
keywords: belinostat; bortezomib; endoplasmic reticulum stress; renal cancer; ubiquitinated protein