Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells

Abstract

Background: Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibitio of histone deacetylase (HDAC) 6 by the HDAC inhibitor panobinostat hinders the refolding of unfolded protein by increasing the acetylation of heat shock protein 90. We investigated whether combining panobinostat with th proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolde proteins, thereby causing ubiquitinated proteins to accumulate and induce ER stress Methods: Caki-1, ACHN, and 769-P cells were treated with panobinostat and/or bortezomib. Cell viability clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluate using a murine subcutaneous xenograft model. The combination-induced ER stress and ubiquitinated protei accumulation were assessed Results: The combination of panobinostat and bortezomib induced apoptosis and inhibited renal cancer growt synergistically (combination indexes <1). It also suppressed colony formation significantly (p <0.05). In a murin subcutaneous tumor model, a 10-day treatment was well tolerated and inhibited tumor growth significantl (p <0.05). Enhanced acetylation of the HDAC6 substrate alpha-Tubulin was consistent with the suppression o HDAC6 activity by panobinostat, and the combination was shown to induce ER stress and ubiquitinated protei accumulation synergistically Conclusions: Panobinostat inhibits renal cancer growth by synergizing with bortezomib to induce ER stress an ubiquitinated protein accumulation. The current study provides a basis for testing the combination in patient with advanced renal cancer.