Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma |
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| Authors: | YanGuo Kong Gustavo A Barisone Ranjit S Sidhu Robert T O’Donnell Joseph M Tuscano |
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| Affiliation: | 1Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, California, United States of America;2Department of Neurosurgery, Peking University Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China;3Department of Veterans Affairs, Northern California Healthcare System, Sacramento, California, United States of America |
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| Abstract: | Checkpoint kinase inhibition has been studied as a way of enhancing the effectiveness of DNA-damaging agents. More recently, histone deacetylase inhibitors have shown efficacy in several cancers, including non-Hodgkin lymphoma. To evaluate the effectiveness of this combination for the treatment of lymphoma, we examined the combination of AR42, a histone deacetylase inhibitor, and checkpoint kinase 2 (CHEK2) inhibitor II in vitro and in vivo. The combination resulted in up to 10-fold increase in potency in five Burkitt lymphoma cell lines when compared with either drug alone. Both drugs inhibited tumor progression in xenograft models, but the combination was more effective than either agent alone, resulting in regression of established tumors. No toxicity was observed. These results suggest that the combination of histone deacetylase inhibition and checkpoint kinase inhibition represent an effective and nontoxic treatment option that should be further explored in preclinical and clinical studies. |
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