The histone deacetylase inhibitor panobinostat is a potent antitumor agent in canine diffuse large B-cell lymphoma
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Joana N.R. Dias1, Sandra I. Aguiar1, Diane M. Pereira2, Ana S. André1, Lurdes Gano3, João D.G. Correia3, Belmira Carrapiço1, Barbara Rütgen4, Rui Malhó5, Conceição Peleteiro1, João Goncalves2, Cecília M.P. Rodrigues2, Solange Gil1, Luís Tavares1 and Frederico Aires-da-Silva1
1Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Lisboa, Portugal
2Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
3Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional, Bobadela LRS, Portugal
4Department of Pathobiology, Clinical Pathology Unit, University of Veterinary Medicine, Vienna, Austria
5Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
Frederico Aires-da-Silva, email: [email protected]
Keywords: HDAC inhibitors; panobinostat; LBH589; non-Hodgkin lymphoma; canine lymphoma
Received: January 15, 2018 Accepted: May 19, 2018 Published: June 19, 2018
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.
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