The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss

Jitesh Pratap, Jacqueline Akech, John J. Wixted, Gabriela Szabo, Sadiq Hussain, Meghan Elizabeth McGee Lawrence, Xiaodong Li, Krystin Bedard, Robinder J. Dhillon, Andre J. Van Wijnen, Janet L. Stein, Gary S. Stein, Jennifer J. Westendorf, Jane B. Lian

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3210-3220
Number of pages11
JournalMolecular cancer therapeutics
Volume9
Issue number12
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

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Osteolysis
Histone Deacetylase Inhibitors
Bone and Bones
Growth
Neoplasms
Bone Development
SCID Mice
vorinostat
Parathyroid Hormone-Related Protein
Osteopontin
Metabolic Bone Diseases
Tumor Burden
Tibia
Interleukin-8
Skeleton
Radiography
Femur
Prostatic Neoplasms
Breast
Extremities

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss. / Pratap, Jitesh; Akech, Jacqueline; Wixted, John J.; Szabo, Gabriela; Hussain, Sadiq; McGee Lawrence, Meghan Elizabeth; Li, Xiaodong; Bedard, Krystin; Dhillon, Robinder J.; Van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.; Westendorf, Jennifer J.; Lian, Jane B.

In: Molecular cancer therapeutics, Vol. 9, No. 12, 01.12.2010, p. 3210-3220.

Research output: Contribution to journalArticle

Pratap, J, Akech, J, Wixted, JJ, Szabo, G, Hussain, S, McGee Lawrence, ME, Li, X, Bedard, K, Dhillon, RJ, Van Wijnen, AJ, Stein, JL, Stein, GS, Westendorf, JJ & Lian, JB 2010, 'The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss', Molecular cancer therapeutics, vol. 9, no. 12, pp. 3210-3220. https://doi.org/10.1158/1535-7163.MCT-10-0572
Pratap, Jitesh ; Akech, Jacqueline ; Wixted, John J. ; Szabo, Gabriela ; Hussain, Sadiq ; McGee Lawrence, Meghan Elizabeth ; Li, Xiaodong ; Bedard, Krystin ; Dhillon, Robinder J. ; Van Wijnen, Andre J. ; Stein, Janet L. ; Stein, Gary S. ; Westendorf, Jennifer J. ; Lian, Jane B. / The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss. In: Molecular cancer therapeutics. 2010 ; Vol. 9, No. 12. pp. 3210-3220.
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AU - McGee Lawrence, Meghan Elizabeth

AU - Li, Xiaodong

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AU - Dhillon, Robinder J.

AU - Van Wijnen, Andre J.

AU - Stein, Janet L.

AU - Stein, Gary S.

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