Increasing evidence supports the role of genetic and epigenetic alterations in a wide variety of human diseases, including
cancer. Assessment of these alterations is hence essential for estimating the hazardous effects of human exposure to medications.
Panobinostat received US Food and Drug Administration's approval in 2015 for treatment of certain
tumors and its usefulness as part of a strategy to treat other diseases, such as human immunodeficiency virus
infection, is currently investigated. Nevertheless, no data on in vivo genotoxical and epigenotoxical effects of
panobinostat are available. The aim of the current study was to assess the genotoxical and epigenotoxical properties of
panobinostat in murine bone marrow cells. Molecular mechanisms underlying these alterations were also evaluated. We show that mice treated with
panobinostat doses recommended for human developed numerical
chromosomal abnormalities, structural chromosomal damage, oxidative DNA damage, and
DNA hypomethylation. These effects were dose-dependent. Further,
panobinostat altered the expression of 23 genes implicated in DNA damage, as determined by RT² Profiler polymerase chain reaction (PCR) array, and confirmed by quantitative real-time PCR and western blotting. Collectively, these findings indicate that
panobinostat exposure induces aneugenicity, clastogenicity, oxidative DNA damage,
DNA hypomethylation, and down-regulation of repair gene expression, which may be responsible for
panobinostat-induced genotoxical and epigenotoxical effects. Considering the potential toxicity of
panobinostat, the medicinal use of
panobinostat must be weighed against the risk of
tumorigenesis and the demonstrated toxicity profile of
panobinostat may support further development of chemotherapeutic treatments with reduced toxicity. Diminishing the metabolic liabilities associated with
panobinostat exposure, and simultaneous use of
panobinostat with DNA repair enhancers, are examples of strategies for drug design to reduce
panobinostat carcinogenicity.