17-beta-estradiol analog inhibits cell proliferation by induction of apoptosis in breast cell lines

Visagie, Michelle Helen; Birkholtz, Lyn‐Marié; Joubert, Annie M.

doi:10.1002/jemt.22334

Cited by 19 publications

(21 citation statements)

References 25 publications

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“…Distorted cell shape, high density of digit-like apical microvilli, formations of vacuoles, lysosomes and apoptotic bodies, heterochromatin, as well as fragmented DNA were detected in both cell lines by means of transmission electron microscopy. This observation is supported by a study where 17β estradiol analog-treated MDA-MB-231, MCF-7 and MCF-12A cells demonstrated the presence of apoptotic bodies and vacuoles [63]. Fragmented nuclei and apoptotic bodies were detected within tumorigenic cells that were exposed to combination compounds, which indicate late stages of apoptosis and also support previous cell cycle- and apoptotic quantification [28,62].…”

Section: Discussionsupporting

confidence: 70%

Synergistic Anticancer Potential of Dichloroacetate and Estradiol Analogue Exerting their Effect via ROS-JNK-Bcl-2-Mediated Signalling Pathways

Stander

Joubert

2015

Cell Physiol Biochem

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Background: C9, a newly in silico-designed inhibitor of microtubule dynamics induces G₂/M arrest culminating in apoptosis. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase, an enzyme that promotes pyruvate entry into mitochondria. The use of antitumor drugs targeting different cancer features can be a more effective way to overcome drug resistance. Methods: The influence of C9 (130 nM) + DCA (7.5 mM) on MCF-7 and MCF-12 cells was assessed via microscopy spectrophotometry global gene expression and flow cytometry assays. Results: An LDH assay showed that C9+DCA treatment decreased cell viability to 83.5% in MCF-7 cells when compared to the non-tumorigenic MCF-12A cells 92.4% (P < 0.05). C9- and C9+DCA treatment induced mitochondrial membrane potential depolarization in MCF-7 cells but not in MCF-12A cells (P < 0.05). The occurrence of apoptosis was associated with increased hypo- and hyper-phosphorylation of Bcl-2 Ser⁷⁰ and caspase 7 activation. Kinase inhibition revealed sustained activation of the JNK pathway caused increased Bcl-2 protein Ser⁷⁰ hypo-and hyper-phosphorylation. Elevated levels of DCF fluorescence was observed in DCA-, C9- and C9+DCA-exposed MCF-7 cells, but not in MCF-12A cells, indicating cytosolic H₂O₂/Fe²⁺ formation in treated tumorigenic cells. LC3-II expression was elevated in C9+DCA-treated cells in both cell lines, indicating that autophagy was also induced. Conclusions: Synergistic effects of C9+DCA were demonstrated on breast carcinoma and non-tumorigenic cells with selectivity towards the MCF-7 cells. Antimitotic compound C9 in combination with a glycolytic inhibitor dichloroacetate eradicates breast cancer cells through ROS-JNK-Bcl-2-mediated signalling pathways in vitro and it is argued that autophagy acts as protective mechanism in the treated cells before apoptosis occurs.

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Section: Discussionsupporting

confidence: 70%

Synergistic Anticancer Potential of Dichloroacetate and Estradiol Analogue Exerting their Effect via ROS-JNK-Bcl-2-Mediated Signalling Pathways

Stander

Joubert

2015

Cell Physiol Biochem

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“…Cells were seeded (1,000,000) in a 25 cm 2 flask with an overnight attachment policy [23]. Subsequently, medium was discarded and cells were exposed to the compounds.…”

Section: Methodsmentioning

confidence: 99%

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

2016

Self Cite

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BackgroundComputer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17β-estradiol metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple myeloma. Owing to 2ME2’s poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2 (1 µM), were assessed on morphology and apoptosis induction in cervical cancer cells.ResultsTransmission electron microscopy, scanning electron microscopy and polarization-optical transmitted light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8 activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower pharmacological concentration (180 nM) compared to 2ME2 (1 µM physiological concentration).ConclusionComputer-based technology is essential in drug discovery and together with in vitro studies for the evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro. Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability while preserving apoptotic activity in vitro.

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“…Studies have indicated that BIRC5 contributes to tumourigenesis and progression of NSCLCs due to its apoptosis suppression functions [32,33]. Moreover, it has been reported that E2 can cause cancer cell apoptosis [34]. Therefore, we speculated that cell apoptosis was enhanced in SCNC after E2 treatment by up-regulating expression of CASP3 and affecting the relationship between CASP3 and IAP members (BIRC2, BIRC3 and BIRC5).…”

Section: Discussionmentioning

confidence: 92%

RNA-Seq analysis for the potential targets and molecular mechanisms of 17 β-estradiol in squamous cell lung carcinoma

Chen¹,

Wü²,

Wang³

et al. 2016

neo

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The efficacy of 17 β-estradiol (E2) was valid in some cancers, while its effects on squamous cell lung carcinoma (SCLC) were still unclear. The aim of our study was to investigate the potential targets and molecular mechanisms of E2 in SCLC cells.Two RNA libraries from human lung carcinoma cells (SK-MES-1) with and without E2 treatment were constructed and sequenced. The differentially expressed genes (DEGs) between cells with or without E2 treatment were identified by cuffdiff software. Hierarchical Clustering Analysis (HCA) was performed for displaying gene expression changes and classification. Furthermore, enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology Biological Process (GO BP) terms were performed through DAVID. The protein-protein interaction (PPI) network was constructed through STRING. Additionally, differentially expressed lncRNAs were also selected by cuffdiff software.Total 129 DEGs including 58 up-and 71 down-regulated genes were obtained. Cancer-related pathways including small cell lung cancer, hypertrophic cardiomyopathy (HCM) and pathways in cancer and biological processes including regulation of phosphorus metabolic process, protein localization and nucleus organization were enriched. The PPI network with 113 nodes and 312 edges was constructed. CASP3, ITGA2, COL4A6, PML and CDC25B were identified as hub nodes which had more interactions with others in the PPI network. Furthermore, eight up-regulated and ten down-regulated lncRNAs were selected.CASP3, ITGA2 and Lnc-DLK1-4:31 (one of down-regulated lncRNAs) might play pivotal roles in E2 treated SCNC cells by influencing cell apoptosis, angiogenesis and cell invasion respectively.Key words: squamous cell lung carcinoma, RNA-Seq, differentially expressed genes, lnc-RNA Squamous cell lung carcinoma (SCLC) is a common type of non-small-cell lung cancer (NSCLC) and the second leading cause of death related to lung cancer which causes approximately 400,000 deaths per year worldwide [1]. SCLC develops mainly in the upper airways and cigarette smokers are more susceptible to SCLC, therefore it is more common in men than in women [2]. Although various therapies such as radiation, chemotherapy, surgery and palliative care have been used for SCLC treatment, the overall therapeutic results were not optimistic [3,4]. A more thorough understanding of the mechanism of SCLC may offer a new hope on treatment innovations and prevention strategies.Estrogens are a group of human sex hormones which can be secreted primarily by the ovaries and placenta in women and the testes in men. The cell response to estrogens is in a concentration-dependent manner. Previous studies found that low concentration of 17 β-estradiol (E2) promoted the development of breast cancer and prostatic cancer, while 10 nM or higher concentration of E2 could cause cancer cell apoptosis [5][6][7]. The three major naturally occurring estrogens are E2, estrone and estriol, among them, E2 is the predominant and most active [8]. Meanwhile, Zhao et al...

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17-beta-estradiol analog inhibits cell proliferation by induction of apoptosis in breast cell lines

Cited by 19 publications

References 25 publications

Synergistic Anticancer Potential of Dichloroacetate and Estradiol Analogue Exerting their Effect via ROS-JNK-Bcl-2-Mediated Signalling Pathways

Synergistic Anticancer Potential of Dichloroacetate and Estradiol Analogue Exerting their Effect via ROS-JNK-Bcl-2-Mediated Signalling Pathways

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

RNA-Seq analysis for the potential targets and molecular mechanisms of 17 β-estradiol in squamous cell lung carcinoma

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