Chemosensitization of osteosarcoma by the histone deacetylase inhibitor valproic acid
Date
2010
Authors
Wittenburg, Luke Anthony, author
Thamm, Douglas, advisor
Withrow, Stephen J., committee member
Gustafson, Daniel, committee member
Ehrhart, E. J., committee member
Munster, Pamela, committee member
Journal Title
Journal ISSN
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Abstract
Osteosarcoma is the most common primary bone tumor in both canines and humans. Since the introduction of adjuvant chemotherapy to treatment protocols in the 1980's there has been very little improvement in long-term survival. The majority of canine patients will succumb to metastatic disease and likewise, this is the primary cause of death in humans with osteosarcoma. This underscores the urgent need for novel therapeutics in the treatment of osteosarcoma. Histone deacetylase inhibitors (HDACi) have recently emerged as a promising class of anti-cancer agents that are rapidly undergoing clinical evaluation in human cancer patients, yet very little information exists on the use of these agents in osteosarcoma. Studies on histone deacetylase inhibitors in canine cancer are even scarcer, and a better understanding of the mechanisms of action is required to generate rational treatment protocols utilizing these drugs in combination with traditional chemotherapy agents. Utilizing a combination of >in vitro assays we have been able to demonstrate that the HDACi valproic acid can sensitize both human and canine osteosarcoma cells to the anti-proliferative and pro-apoptotic effects of the DNA-targeting chemotherapeutic agent doxorubicin. We confirmed this finding in a xenograft model of canine osteosarcoma which showed a significant delay in tumor growth associated with increased apoptosis and decreased tumor cell proliferation. These observations confirmed that, as in previously reported studies on human cancer cells, synergistic anti-tumor activity can be attained with the combination of valproic acid and doxorubicin. We additionally sought to determine a maximum tolerated dose of valproic acid that can be administered to tumor-bearing dogs for 48 hours prior to a standard dose of doxorubicin. We discovered that the combination is well tolerated and that a biologically effective dose can be achieved without significant toxicity. In addition we showed that there were no effects on doxorubicin pharmacokinetics or potentiation of side effects when valproic acid was given prior to doxorubicin. Lastly, through gene expression microarray and pathway analysis we identify the molecular pathways that are most affected by valproic acid treatment in OS cells and were able to confirm these results with a combination of quantitative real time RT-PCR and functional/biochemical assays, providing additional information on potential therapeutic modalities to combine with HDACi. The combination of studies presented herein provide evidence that canine and human OS cells have similar molecular responses to HDAC inhibition and provide further rationale for the use of spontaneously occurring OS in dogs as a model system for the human disease.
Description
Rights Access
Subject
histone deacetylase
Osteosarcoma -- Chemotherapy
valproic acid
Dogs -- Diseases
osteosarcoma
Histone deacetylase -- Inhibitors
Bones -- Tumors
Valproic acid -- Physiological effect