Tempol prevents genotoxicity induced by vorinostat: role of oxidative DNA damage

Abstract

Vorinostat is a member of histone deacetylase inhibitors, which represents a new class of anticancer agents for the treatment of solid and hematological malignancies. Studies have shown that these drugs induce DNA damage in blood lymphocytes, which is proposed to be due to the generation of oxidative lesions. The increase in DNA damage is sometimes associated with risk of developing secondary cancer. Thus, finding a treatment that limits DNA damage caused by anticancer drugs would be beneficial. Tempol is a potent antioxidant that was shown to prevent DNA damage induced by radiation. In this study, we aimed to investigate the harmful effects of vorinostat on DNA damage, and the possible protective effects of tempol against this damage. For that, the spontaneous frequency of sister chromatid exchanges (SCEs), chromosomal aberrations (CAs), and 8-hydroxy-2-deoxy guanosine (8-OHdG) levels were measured in cultured human lymphocytes treated with vorinostat and/or tempol. The results showed that vorinostat significantly increases the frequency of SCEs, CAs and 8-OHdG levels in human lymphocytes as compared to control. These increases were normalized by the treatment of cells with tempol. In conclusion, vorinostat is genotoxic to lymphocytes, and this toxicity is reduced by tempol. Such results could set the stage for future studies investigating the possible usefulness of antioxidants co-treatment in preventing the genotoxicity of vorinostat when used as anticancer in human.

Epigenetics of Alzheimer's Disease and Frontotemporal Dementia

“…Therefore, the use of SAHA may increase risk of cancer. However, a very recent study showed that the antioxidant Tempol prevents genotoxicity induced by SAHA and may, potentially, alleviate the long-term risks of the drug [147]. Hence, further detailed studies are required to develop safe and effective treatment protocols using DNMTi and HDACi.…”

Vorinostat Pretreatment Enhanced Ciprofloxacin-Induced Antibacterial Activity

“…We have recently shown that vorinostat induce oxidative chromosomal damage leading its mutagenic effect in blood lymphocytes [19]. Given the importance of reactive oxygen species, energy metabolism, mitochondrial functions for the antibacterial action of floroquinolones [5][6][7]17], it is probable that these mechanisms has a role in the observed enhancement of ciprofloxacin antibacterial activity by vorinostat.…”

“…Recently, we showed that the antibacterial activity of ciprofloxacin is altered by major antioxidants, such as, vitamins E and C [17], tempol, pentoxifylline and melatonin [18]. Given that ciprofloxacin acts by inducement of bacterial oxidative damage [5,6], and the known oxidative cell-damaging activity of vorinostat [19], it is likely that vorinostat pretreatmnet enhances ciprofloxacin antibacterial activity.…”

Assessment of genotoxicity of waterpipe smoking using 8-OHdG biomarker

“…Participants' demographics were obtained using a self-administered questionnaire. The level of dependence on waterpipe smoking was mea-sured using the Lebanon Waterpipe Dependence Scale-11 as previously described (Salameh et al, 2008;Alzoubi et al, 2014a). Investigators were available to answer participants' questions when the questionnaires were filled out and the scaling was conducted.…”

“…Levels of 8-OHdG in the samples were determined using an enzyme-linked immunosorbent assay (ELISA) (8-OH-dG EIA kit; Abcam, Cambridge, UK) according to the manufacturer instructions and as previously described (Alzoubi et al, 2013(Alzoubi et al, , 2014a. Samples were assayed in duplicate.…”