TY - JOUR
T1 - The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss
AU - Pratap, Jitesh
AU - Akech, Jacqueline
AU - Wixted, John J.
AU - Szabo, Gabriela
AU - Hussain, Sadiq
AU - McGee-Lawrence, Meghan E.
AU - Li, Xiaodong
AU - Bedard, Krystin
AU - Dhillon, Robinder J.
AU - Van Wijnen, Andre J.
AU - Stein, Janet L.
AU - Stein, Gary S.
AU - Westendorf, Jennifer J.
AU - Lian, Jane B.
PY - 2010/12
Y1 - 2010/12
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-10-0572
DO - 10.1158/1535-7163.MCT-10-0572
M3 - Article
C2 - 21159607
AN - SCOPUS:78650506912
SN - 1535-7163
VL - 9
SP - 3210
EP - 3220
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -