Abstract
IntroductionResearch involving antimitotic compounds identified 2-methoxyestradiol (2ME2), as a promising anticancer endogenous metabolite. Owing to its low bioavailability, several in silico-designed 2ME2 analogues were synthesized. Structure-activity relationship studies indicated that an already existing 17-β-estradiol analogue, namely (8R,13S,14S,17S)-2-ethyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrane-3,17-diyl bis(sulphamate) (EMBS) to exert potential in vitro anticancer activity.MethodsThis study investigated the in vitro apoptotic influence of EMBS in an estrogen receptor-positive breast adenocarcinoma epithelial cell line (MCF-7); an estrogen receptor-negative breast epithelial cell line (MDA-MB-231) and a non-tumorigenic breast cell line (MCF-12A). Cell cycle progression, a phosphatidylserine flip, caspase 6-, 7- and 8 enzyme activity levels, Bcl-2 phosphorylation status at serine 70 and Bcl-2- and p53 protein levels were investigated to identify a possible action mechanism for apoptotic induction.ResultsThe xCELLigence real-time label-independent approach revealed that EMBS exerted antiproliferative activity in all three cell lines after 24 h of exposure. A G2M block was observed and apoptosis induction was verified by means of flow cytometry using propidium iodide and Annexin V-FITC respectively. EMBS-treated cells demonstrated a reduced mitochondrial membrane potential. EMBS exposure resulted in a statistically significant increase in p53 protein expression, decreased Bcl-2 protein expression and a decrease in pBcl-2(s70) phosphorylation status in all three cell lines. Results support the notion that EMBS induces apoptosis in all three cell lines.ConclusionThis study includes investigation into the apoptotic hallmarks exerted by EMBS after exposure of three cell lines namely MCF-7-, MDA-MDA-231- and MCF-12A cells. Increased caspase 6-, caspase 7- and caspase 8 activities, upregulation of p53 protein expression and a decrease in phosphorylation status of Bcl-2 at serine 70 in tumorigenic and non-tumorigenic lines were demonstrated.
Highlights
Research involving antimitotic compounds identified 2-methoxyestradiol (2ME2), as a promising anticancer endogenous metabolite
Apoptosis was indicated by the existence of a sub-G1 phase after exposure to 0.4 μM EMBS for 24 h in MCF-7, MDA-MB-231 and MCF-12A cells (Figures 2, 3 and Table 1)
Results indicated that EMBS exposure resulted in increased caspase 6, caspase 7- and caspase 8 activity when compared to vehicle-treated cells
Summary
Research involving antimitotic compounds identified 2-methoxyestradiol (2ME2), as a promising anticancer endogenous metabolite. For decades antimitotic agents have been studied for their potential anticancer activity These studies have resulted in the discovery of 2-methoxyestradiol (2ME2), an endogenous 17β-estradiol that exerts antiproliferative, antiangiogenic, and anti-inflammatory activity in an estrogen receptor-independent manner [1]. In structure-activity relationship studies it has been reported that the addition of sulphamate groups (position 3 and 17) to 2ME2 results in superior efficacy and bioavailability [2]. This improvement is due to the sulphamate groups inhibiting activation of metabolism and deactivation of conjugation and interaction with carbonic anhydrase [4]. The superior bioavailability is supported by a bis-sulphamoylated analogue
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