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A Bioinformatics Pipeline for Investigating Molecular Evolution and Gene Expression using RNA-seq
Published on: May 28, 2021
Investigation of belinostat-induced genomic instability by molecular cytogenetic analysis and pathway-focused gene
S M Attia1, M A Al-Hamamah2, M R Alotaibi2
1Pharmacology & Toxicology Department, Faculty of Pharmacy, King Saud University, P.O. 2457, Riyadh 11451, Saudi Arabia; Pharmacology & Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Abstract:
Histone deacetylases (HDACs), which regulate transcription and specific functions such as tumor suppression by p53, are frequently altered in tumors and have a contentious role in carcinogenesis. HDAC inhibitors, which have a long history of use in psychiatry and neurology, have recently been tested as possible treatments for tumors. Belinostat received regulatory approval in the USA on July 3, 2014, for use against peripheral T-cell lymphoma. However, the unavailability of information on belinostat genotoxicity in normal cells and the molecular mechanisms involved in the genetic instability after exposure to belinostat encouraged us to conduct this study. Our data showed that the exposure of mice to belinostat at the recommended human doses induced chromosome breakage, whole-chromosome lagging, and oxidative DNA damage in bone marrow cells in a dose-dependent manner. The expression levels of 84 genes involved in the DNA damage signaling pathway were evaluated by using an RT2 Profiler PCR array. Belinostat exposure altered the expression of 25 genes, with statistically significant changes observed in 17 genes. The array results were supported by RT-PCR and western blotting experiments. Collectively, our results showed that belinostat exposure caused oxidative DNA damage and downregulated the expression of genes involved in DNA damage repair, which may be responsible for belinostat-induced genomic instability. Thus, the clinical usage of this drug should be weighed against the hazards of carcinogenesis, and the observed genotoxicity profile of belinostat may support further development of efficient HDAC inhibitors with weaker genotoxicity.
Insights
Belinostat, an HDAC inhibitor, causes DNA damage and genomic instability in mice by downregulating DNA repair genes. This genotoxicity necessitates careful consideration of its clinical use and guides the development of safer HDAC inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Histone deacetylases (HDACs) regulate gene expression and tumor suppression, with altered roles in carcinogenesis.
- HDAC inhibitors are explored for cancer treatment, with belinostat approved for peripheral T-cell lymphoma.
- Limited data exists on belinostat's genotoxicity and its mechanisms in normal cells.
Purpose of the Study:
- To investigate belinostat's genotoxicity in normal mouse bone marrow cells.
- To elucidate the molecular mechanisms underlying belinostat-induced genetic instability.
- To assess the impact of belinostat on DNA damage and repair pathways.
Main Methods:
- Mice were exposed to belinostat at recommended human doses.
- Chromosome aberrations and DNA damage in bone marrow cells were analyzed.
- Gene expression profiling of DNA damage signaling pathways was performed using RT2 Profiler PCR array.
- RT-PCR and western blotting validated array findings.
Main Results:
- Belinostat induced chromosome breakage, whole-chromosome lagging, and oxidative DNA damage in a dose-dependent manner.
- Expression of 17 out of 25 altered genes in the DNA damage pathway showed statistically significant changes.
- Belinostat exposure downregulated genes involved in DNA damage repair.
Conclusions:
- Belinostat exposure causes oxidative DNA damage and genomic instability.
- Downregulation of DNA damage repair genes contributes to belinostat-induced genotoxicity.
- Clinical use of belinostat requires balancing benefits against carcinogenesis risks; its genotoxicity profile may inform development of safer HDAC inhibitors.
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