Effect of antioxidants on the genotoxicity of phenethyl isothiocyanate

Abstract

Isothiocyanates are plant-derived compounds that may be beneficial in the prevention of certain chronic diseases. Yet, by stimulating the production of reactive oxygen species (ROS), isothiocyanates can be genotoxic. Whether antioxidants influence isothiocyanate-induced genotoxicity is unclear, but this situation was clarified appreciably herein. In HCT116 cells, phenethyl isothiocyanate (PEITC) increased ROS production, which was inhibited by N-acetylcysteine (NAC) and deferoxamine (DFO) but not by ascorbic acid (ASC) and trolox (TRX) that were found to be more potent radical scavengers. Surprisingly, ASC and TRX each intensified the DNA damage that was caused by PEITC, but neither ASC nor TRX by themselves caused any DNA damage. In contrast, NAC and DFO each not only attenuated PEITC-induced DNA damage but also attenuated the antioxidant-intensified, PEITC-induced DNA damage. To determine if the DNA damage could be related to possible changes in the major antioxidant defence system, glutathione (GSH) was investigated. PEITC lowered GSH levels, which was prevented by NAC, whereas ASC, TRX and DFO neither inhibited nor enhanced the GSH-lowering effect of PEITC. The GSH synthesis inhibitor, buthionine sulphoxime, intensified PEITC-induced DNA damage, although by itself buthionine sulphoxime did not directly cause DNA damage. The principal findings suggest that ASC and TRX make PEITC more genotoxic, which might be exploited in killing cancer cells as one approach in killing cancer cells is to extensively damage their DNA so as to initiate apoptosis.

Mechanism of selective anticancer activity of isothiocyanates relies on differences in DNA damage repair between cancer and healthy cells

“…Similarly, in prostate cancer cells, activation of DNA damage checkpoint kinases preceded peak of ROS formation [9,12]. Strikingly, ascorbic acid or trolox did not attenuate PEITC-induced DNA damage in HCT116 colon cancer cells [11]. Thus, it seems that oxidative stress, even if contributes to ITCs cytotoxicity, might not be a key factor affecting DNA integrity in ITC-treated cells which is also in agreement with our results (Fig.…”

“…[5,9,10,19]. As γH2A.X histone is a marker of DSB, it was believed that ITCs induce this kind of DNA damage, which was also confirmed by comet assays [11] or constant field gel electrophoresis of DNA (CFGE) [10]. Results presented in this work also indicate that SFN and PEITC induce DSB in prostate cancer and to lesser extent-in normal cells.…”

“…Double-strand breaks (DSB) and homologous recombination repair induction have been observed in HeLa cells treated with SFN (10-50 µM) [10]. PEITC induced DNA damage in HCT116 and HT29 colon cancer cells [11].…”

Iron depletion in HCT116 cells diminishes the upregulatory effect of phenethyl isothiocyanate on heme oxygenase-1

“…PEITC can induce oxidative stress, as evidenced by greater ROS production in cells that have been incubated with PEITC [Xiao et al, 2006;Powolny and Singh, 2010]. We recently reported that DFO inhibited the induction of ROS production in PEITC-treated HCT116 cells [Hoffman et al, 2015], which 396 would suggest an involvement of iron in facilitating the production of ROS as caused by PEITC.…”

“…The oxidative stress known to be induced by PEITC [Xiao et al, 2006;Powolny and Singh, 2010;Hoffman et al, 2015] and the resulting upregulation of HO-1 expression could be the consequence of an effect of PEITC on intracellular glutathione, which is an important thiol antioxidant. When HCT116 cells were incubated with PEITC, the levels of glutathione were lowered.…”