The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss
Department of Cell Biology; Department of Medicine; Department of Orthopedics and Physical Rehabilitation
Animals; Bone Neoplasms; Bone Resorption; Bone and Bones; Cell Line, Tumor; Cell Proliferation; Extremities; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Mice; Mice, SCID; Osteolysis; Tumor Burden; Tumor Microenvironment; Xenograft Model Antitumor Assays
Vorinostat, an oral histone deacetylase inhibitor with antitumor activity, is in clinical trials for hematologic and solid tumors that metastasize and compromise bone structure. Consequently, there is a requirement to establish the effects of vorinostat on tumor growth within bone. Breast (MDA-231) and prostate (PC3) cancer cells were injected into tibias of SCID/NCr mice and the effects of vorinostat on tumor growth and osteolytic disease were assessed by radiography, micro-computed tomography, and histologic and molecular analyses. Vorinostat-treated and control mice without tumors were also examined. Tumor growth in bone was reduced approximately 33% by vorinostat with inhibited osteolysis in the first few weeks of the experiment. However, osteolysis became more severe in both the vehicle and vorinostat-treated groups. Vorinostat increased the expression of tumor-derived factors promoting bone resorption, including PTHrP, IL-8, and osteopontin. After 4 weeks of vorinostat therapy, the non-tumor-bearing contralateral femurs and limbs from vorinostat-treated tumor-free SCID mice showed significant bone loss (50% volume density of controls). Thus, our studies indicate that vorinostat effectively inhibits tumor growth in bone, but has a negative systemic effect reducing normal trabecular bone mass. Vorinostat treatment reduces tumor growth in bone and accompanying osteolytic disease as a result of decreased tumor burden in bone. However, vorinostat can promote osteopenia throughout the skeleton independent of tumor cell activity.
DOI of Published Version
Mol Cancer Ther. 2010 Dec;9(12):3210-20. Link to article on publisher's site
Molecular cancer therapeutics
Pratap, Jitesh; Akech, Jacqueline; Wixted, John J.; Szabo, Gabriela; Hussain, Sadiq; McGee-Lawrence, Meghan E.; Li, Xiaodong; Bedard, Krystin; Dhillon, Robinder J.; Van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.; Westendorf, Jennifer J.; and Lian, Jane B., "The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss" (2010). Cell and Developmental Biology Publications. 108.