Genetic and epigenetic alterations induced by the small-molecule panobinostat: A mechanistic study at the chromosome and gene levels

Mohammed A Al-Hamamah; Moureq R Alotaibi; Sheikh F Ahmad; Mushtaq A Ansari; Mohamed S M Attia; Ahmed Nadeem; Saleh A Bakheet; Homood M As Sobeai; Sabry M Attia

doi:10.1016/j.dnarep.2019.03.008

Genetic and epigenetic alterations induced by the small-molecule panobinostat: A mechanistic study at the chromosome and gene levels

DNA Repair (Amst). 2019 Jun:78:70-80. doi: 10.1016/j.dnarep.2019.03.008. Epub 2019 Mar 23.

Authors

Mohammed A Al-Hamamah¹, Moureq R Alotaibi¹, Sheikh F Ahmad¹, Mushtaq A Ansari¹, Mohamed S M Attia², Ahmed Nadeem¹, Saleh A Bakheet¹, Homood M As Sobeai¹, Sabry M Attia³

Affiliations

¹ College of Pharmacy, Pharmacology and Toxicology Department, King Saud University, Riyadh, Saudi Arabia.
² College of Pharmacy, Undergraduate Student, Ain Shams University, Cairo, Egypt.
³ College of Pharmacy, Pharmacology and Toxicology Department, King Saud University, Riyadh, Saudi Arabia; College of Pharmacy, Pharmacology and Toxicology Department, Al-Azhar University, Cairo, Egypt. Electronic address: attiasm@ksu.edu.sa.

PMID: 30978576
DOI: 10.1016/j.dnarep.2019.03.008

Abstract

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.

Keywords: Aneugen; Carcinogen; Clastogen; DNA damage and repair; DNA hypomethylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chromosomes, Mammalian / drug effects*
Chromosomes, Mammalian / genetics*
DNA Breaks / drug effects
DNA Methylation / drug effects
Epigenesis, Genetic / drug effects*
Male
Mice
Mutagens / toxicity*
Oxidation-Reduction / drug effects
Panobinostat / toxicity*
Transcriptome

Substances

Mutagens
Panobinostat