Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

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. online address: http://www.molmed.org

The histone deacetylase inhibitor panobinostat is a potent antitumor agent in canine diffuse large B-cell lymphoma

“…Moreover, the toxicity of conventional chemotherapy often limits its efficacy. Therefore, there has been an increasing interest in the design and development of novel target-specific molecules over the past years [ 16 ]. Owing to shared molecular, incidence, genetic, histopathologic and clinical features, canine lymphoma has been proposed as a comparative animal model for the research of novel therapeutic agents and approaches for human NHL [ 17 – 20 ].…”

Immunotherapeutic Strategies for Canine Lymphoma: Changing the Odds Against Non-Hodgkin Lymphoma

“…The highest incidence rates are found in Australia/New Zealand, Northern America, and Europe. In the United States, NHL is the seventh most common and sixth most common cause of cancer-related death, in Europe is the eleventh most common and the fourteenth most deadly malignancy and its incidence has nearly doubled since the early 70s ( 47 , 48 ). NHL represents 90% of all lymphomas and encompasses an heterogeneous group of cancers characterized by the proliferation of malignant lymphocytes, 85–90% of which arise from B lymphocytes, whereas the remaining derive from T cells or natural killer cells.…”

“…Response rates to conventional chemotherapy are generally >50%; however, most patients eventually relapse. Moreover, the toxicity of conventional chemotherapy often limits its efficacy ( 47 ).…”

Celecoxib Prevents Doxorubicin-Induced Multidrug Resistance in Canine and Mouse Lymphoma Cell Lines

“…Canine lymphomas and human non-Hodgkin lymphomas (NHLs) show strong similarities in genetics, therapy response, histopathology, and disease progression [1][2][3][4][5]. Spontaneously occurring canine lymphoma has been considered a comparative animal model to study mechanisms underlying therapy resistance and to investigate novel therapeutic agents for human NHLs [6,7].…”