Sulphamoylated Estradiol Analogue Induces Reactive Oxygen Species Generation to Exert Its Antiproliferative Activity in Breast Cancer Cell Lines

Abstract

2-Methoxyestradiol (2ME), a 17β-estradiol metabolite, exerts anticancer properties in vitro and in vivo. To address 2ME’s low bioavailability, research led to the in silico design of sulphamoylated 2ME analogues. However, the role of oxidative stress induced in the activity exerted by sulphamoylated compounds remains elusive. In the current study, the influence of 2-Ethyl-17-oxoestra-1,3,5(10)-trien-3-yl sulphamate (ESE-one) on reactive oxygen species (ROS) induction and its effect on cell proliferation, as well as morphology, were assessed in breast tumorigenic cells (MCF-7 and MDA-MB-231). Fluorescent microscopy showed that sulphamoylated estradiol analogues induced hydrogen peroxide and superoxide anion, correlating with decreased cell growth demonstrated by spectrophotometry data. ESE-one exposure resulted in antiproliferation which was repressed by tiron (superoxide inhibitor), trolox (peroxyl inhibitor) and N,N′-dimethylthiourea (DMTU) (hydrogen peroxide inhibitor). Morphological studies demonstrated that tiron, trolox and DMTU significantly decreased the number of rounded cells and shrunken cells in MCF-7 and MDA-MB-231 cells induced by ESE-one. This in vitro study suggests that ESE-one induces growth inhibition and cell rounding by production of superoxide anion, peroxyl radical and hydrogen peroxide. Identification of these biological changes in cancer cells caused by sulphamoylated compounds hugely contributes towards improvement of anticancer strategies and the ROS-dependent cell death pathways in tumorigenic breast cells.

Dysregulation of Catalase by a Sulphamoylated Estradiol Analogue Culminates in Antimitotic Activity and Cell Death Induction in Breast Cancer Cell Lines

“…Sulfamoylated estradiol analogs have been explored in recent years and studies have reported that these derivatives exert antiproliferative and antimitotic activity resulting in cell death induction in various tumorigenic cell lines [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Recent studies have demonstrated that ESE-one possesses antiproliferative activity that is dependent on oxidative stress induced by increased peroxyl radical, superoxide anion and hydrogen peroxide [ 9 ]. However, the role of these reactive oxygen species on mitochondrial membrane potential and cell cycle progression remain unknown as well as the role of possible dysregulation of antioxidant enzymes by the sulfamoylated estradiol compound in breast tumorigenic cell lines.…”

“…Previous research has indicated that sulfamoylated estradiol compounds exert antiproliferative and antimitotic activity in several tumorigenic cell lines [ 7 ]. Recent findings reported that ESE-one, a representative sulfamoylated estradiol analog, reduces cell growth and induces cell rounding by means of increased quantities of superoxide anion, peroxyl radical and hydrogen peroxide [ 9 ]. The current study suggests that ESE-one induces a time-dependent accumulation of cells in the G 2 /M and G 1 phase that is partially impaired by tiron and trolox and DMTU suggesting that superoxide anion, hydrogen peroxide and peroxyl radical is required for the effects exerted by ESE-one resulting in antimitotic activity and induction of cell death.…”

“…Previous studies have been performed which indicated that these scavengers inhibited the antiproliferative activity induced by ESE-one in a dose-dependent manner. The concentrations of the scavengers used in this study are 5 mM tiron, 8 mM DMTU or 80 µM trolox since the previous experiments indicated that scavengers inhibited the antiproliferative activity exerted by ESE-one optimally at these doses [ 9 ].…”

“…Furthermore, these effects exerted by ESE-one were inhibited by tiron, N , N ’-dimethylthiourea (DMTU) and trolox indicating that the activity induced by ESE-one is dependent on the generation of superoxide anion, peroxyl radical and hydrogen peroxide. In addition, scavenging of hydroxyl radical, nitric oxide and singlet oxygen did not have any significant influence on the activity induced by ESE-one suggesting that these reactive oxygen species are not essential for the effects demonstrated by ESE-one [ 9 ]. However, the influence of ESE-one on the innate antioxidant system including superoxide dismutase (SOD) and catalase remains unknown.…”

Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma

“…Compared with BTZ alone, representing the first PI available for MM patients, they showed that 2-methoxyestradiol (2ME), which is a natural estrogen metabolite, induced a higher rate of MM cell death, due to increases in the mitochondrial ROS and Ca 2+ levels in the cells, the activation of c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase kinase 4/7 (MKK4/7) [ 17 ]. The capability of 2ME to increase the death of cancer cells has also been proved to be powerful against other types of tumor, such as ovarian, lung, breast, and colorectal tumors [ 13 , 18 , 19 , 20 , 21 ].…”