title: The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss.
abstract: 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 ∼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.
authors.affiliation: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Jitesh
authors.initials: J
authors.lastname: Pratap
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Akech
authors.forename: John J
authors.initials: JJ
authors.lastname: Wixted
authors.forename: Gabriela
authors.initials: G
authors.lastname: Szabo
authors.forename: Sadiq
authors.initials: S
authors.lastname: Hussain
authors.forename: Meghan E
authors.initials: ME
authors.lastname: McGee-Lawrence
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Krystin
authors.initials: K
authors.lastname: Bedard
authors.forename: Robinder J
authors.initials: RJ
authors.lastname: Dhillon
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D001862:Bone Resorption / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005121:Extremities / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D010014:Osteolysis / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D011859:Radiography; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat