Abstract
Non-Hodgkin lymphoma (NHL) is one of the most common causes of cancer-related death in the United States and Europe. Although the outcome of NHL patients has improved over the last years with current therapies, the rate of mortality is still high. A plethora of new drugs is entering clinical development for NHL treatment; however, the approval of new treatments remains low due in part to the paucity of clinically relevant models for validation. Canine lymphoma shares remarkable similarities with its human counterpart, making the dog an excellent animal model to explore novel therapeutic molecules and approaches.Histone deacetylase inhibitors (HDACis) have emerged as a powerful new class of anti-cancer drugs for human therapy. To investigate HDACi antitumor properties on canine diffuse large B-cell lymphoma, a panel of seven HDACi compounds (CI-994, panobinostat, SBHA, SAHA, scriptaid, trichostatin A and tubacin) was screened on CLBL-1 canine B-cell lymphoma cell line. Our results demonstrated that all HDACis tested exhibited dose-dependent inhibitory effects on proliferation of CLBL-1 cells, while promoting increased H3 histone acetylation. Amongst all HDACis studied, panobinostat proved to be the most promising compound and was selected for further in vitro and in vivo evaluation. Panobinostat cytotoxicity was linked to H3 histone and α-tubulin acetylation, and to apoptosis induction. Importantly, panobinostat efficiently inhibited CLBL-1 xenograft tumor growth, and strongly induced acetylation of H3 histone and apoptosis in vivo. In conclusion, these results provide new data validating HDACis and, especially, panobinostat as a novel anti-cancer therapy for veterinary applications, while contributing to comparative oncology.
Highlights
It has become evident that the importance of small companion animals in the “One Medicine” concept goes beyond their role as reservoirs for infectious diseases and their contribution to human health through the human-companion animal bond
When compared with other animal models, the canine model presents unique advantages: diseases are naturally occurring in immune-competent hosts; the size of the animals allows testing therapeutic approaches similar to the ones used in humans; disease mapping and pharmacogenomics are simplified by the organization of dogs into isolated populations with reduced genetic variation; the relatively fast disease progression rate allows obtaining early conclusions from clinical trials; and the social status of dogs as companion animal allows them to benefit from high quality health care and the ethical exploration of translational approaches [3,4,5]
Histone deacetylase inhibitors (HDACis) suppress cell proliferation and present cytotoxic effects on canine lymphoma Aiming to evaluate the potential cytotoxic effects of HDACis on canine lymphoma we have tested a panel of seven compounds with HDACi activity - CI-994, panobinostat, SBHA, SAHA, scriptaid, trichostatin A and tubacin - in the well-characterized CLBL-1 cell line
Summary
It has become evident that the importance of small companion animals in the “One Medicine” concept goes beyond their role as reservoirs for infectious diseases and their contribution to human health through the human-companion animal bond. Efforts towards bringing together veterinary and human medicine for the comparative research of cancer are being pursued [6] These initiatives are motivated by the increasing healthcare standards demanded by pet owners, originating the need for novel cancer therapies in veterinary settings [7,8,9]. Human NHL represents 90% of all lymphomas and 85–90% of cases arise from B lymphocytes This group of malignancies usually develops in the lymph nodes, but can occur in almost any tissue, ranging from the more indolent follicular lymphoma to the more aggressive diffuse large B-cell (DLBCL) and Burkitt’s lymphoma [13]. 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 [17,18,19,20]. There is an urgent need to develop new treatment strategies in veterinary medicine for refractory disease [21]
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