Abstract
INTRODUCTION AND OBJECTIVES: Inducing endoplasmic reticulum (ER) stress is a novel approach to cancer therapy. The HIV protease inhibitor ritonavir induces ER stress by activating the unfolded protein response and we hypothesized that combining the proteasome inhibitor bortezomib with ritonavir would enhance this stress by inhibiting the degradation of unfolded proteins. METHODS: The viability and clonogenicity of the prostate cancer cells (LNCaP, PC3, and DU145) treated with ritonavir (25–50 M) and bortezomib (5–10 nM) were assessed by MTS assay and colony formation assay. The in vivo efficacy of the combination was evaluated using a murine subcutaneous tumor model using PC3 cells. Annexin-V assay was used to detect apoptosis. Induction of ER stress, histone acetylation, and the expression of p21 and apoptosis-associated proteins were evaluated by western blot analysis. RESULTS: The combination of ritonavir and bortezomib induced apoptosis and inhibited the prostate cancer growth synergistically. It also inhibited colony formation. In subcutaneous tumor models, 10-day treatment with the combination was well tolerated and inhibited tumor growth. The combination induced ER stress synergistically, as evidenced by the increased expression of glucose-regulated protein 78, heat shock protein 70, and cyclic AMP response element binding protein 2 (CREB2). It also induced histone acetylation and thereby increased p21 expression. This histone acetylation is attributable to the increased CREB2 expression because CREB2 is also a histone acetyltransferase. In addition, decreased expression of histone deacetylases by the combination was thought to enhance this histone acetylation. CONCLUSIONS: The combination of ritonavir and bortezomib induces apoptosis and inhibits the proliferation of prostate cancer cells by inducing ER stress. Our results provide a rationale for investigating this combination in patients with prostate cancer.
Published Version
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