Signaling Pathways of ESE-16, an Antimitotic and Anticarbonic Anhydrase Estradiol Analog, in Breast Cancer Cells

Stander, Barend André; Joubert, Fourie; Tu, Chingkuang; Sippel, Katherine H.; McKenna, Robert; Joubert, Annie M.

doi:10.1371/journal.pone.0053853

Cited by 22 publications

(59 citation statements)

References 64 publications

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“…Our preliminary data showed that the antiproliferative effect of ESE-16 is more potent on malignant cell lines than on non-tumorigenic cells [32]. The selectivity of ESE-16 towards metastatic breast cancer cells (MDA-MB-231) and breast adenocarcinoma MCF-7 cells was demonstrated in a comparison to its behavior toward non-tumorigenic MCF-12A cells [32].…”

Section: Introductionmentioning

confidence: 79%

“…This was then followed with 24 h exposure under the same conditions. Appropriate controls were included: cells propagated in growth medium only; and a vehicle control composed of cells treated with DMSO with a final dilution never exceeding 0.02% (v/v) [32,33]. Actinomycin D (0.1 µg/ml in growth medium) was used as a positive control for the induction of apoptosis [33].…”

Section: General Cell Culture Proceduresmentioning

confidence: 99%

“…The selectivity of ESE-16 towards metastatic breast cancer cells (MDA-MB-231) and breast adenocarcinoma MCF-7 cells was demonstrated in a comparison to its behavior toward non-tumorigenic MCF-12A cells [32]. The aim of this study was to establish whether ESE-16 inhibits cell proliferation via autophagy and apoptosis in esophageal carcinoma.…”

Section: Introductionmentioning

confidence: 99%

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Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells

Wolmarans

Mqoco

Stander

et al. 2014

Cellular and Molecular Biology Letters

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Abstract:Cancer is the second leading cause of death in South Africa. The critical role that microtubules play in cell division makes them an ideal target for the development of chemotherapeutic drugs that prevent the hyperproliferation of cancer cells. The new in silico-designed estradiol analogue 2-ethyl-3-Osulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) was investigated in terms of its in vitro antiproliferative effects on the esophageal carcinoma SNO cell line at a concentration of 0.18 µM and an exposure time of 24 h. Polarization-optical differential interference contrast and triple fluorescent staining (propidium iodide, Hoechst 33342 and acridine orange) revealed a decrease in cell density, metaphase arrest, and the occurrence of apoptotic bodies in the ESE-16-treated cells when compared to relevant controls. Treated cells also showed an increase in the presence of acidic vacuoles and lysosomes, suggesting the occurrence of autophagic processes. Cell death via autophagy was confirmed using the Cyto- . In addition, a reduction in mitochondrial membrane potential was also observed, which suggests the involvement of apoptotic cell death induced by ESE-16 via the intrinsic apoptotic pathway. In this study, it was demonstrated that ESE-16 induces cell death via both autophagy and apoptosis in esophageal carcinoma cells. This study paves the way for future investigation into the role of ESE-16 in ex vivo and in vivo studies as a possible anticancer agent.

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Section: Introductionmentioning

confidence: 79%

Section: General Cell Culture Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells

Wolmarans

Mqoco

Stander

et al. 2014

Cellular and Molecular Biology Letters

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“…The altered mitochondrial membrane potential were detected by MitoCapture™ apoptosis detection kit produced by BioVision Inc. (Mountain View, CA, USA) as described previously [10]. Cells were cultured for 24 h and were exposed to compounds compounds (130 nM C9, 7.5 mM DCA and C9+DCA) for 24 h respectively.…”

Section: Methodsmentioning

confidence: 99%

“…C9 is another sulphamoylated analogue of 2ME and was in silico designed by our group [8,9,10]. C9 has improved bioavailability because of the ability of the sulphamoyl moiety to reversibly bind to carbonic anhydrase II present in erythrocytes and, in turn, this allows C9 to circumvent liver metabolism [11.]…”

Section: Introductionmentioning

confidence: 99%

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

Visagie

Birkholtz

Joubert

2014

Microsc. Res. Tech.

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Microtubules are important targets when studying potential anticancer agents since disturbance of these microtubule dynamics results in cell cycle arrest and cell death.2-Methoxyestradiol is a naturally occurring metabolite that exerts antiproliferative activity and induces apoptosis. Due to limited biological accessibly and rapid metabolic degradation, several analogues were synthesized. This study investigated the antiproliferative influence of an 2-methoxyestradiol analogue, (8R, 13S, 14S, 17S)-2-Ethyl- 13-methyl-7, 8, 9, 11, 12,13, 14, 15, 16, 17-

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Signaling Pathways of ESE-16, an Antimitotic and Anticarbonic Anhydrase Estradiol Analog, in Breast Cancer Cells

Cited by 22 publications

References 64 publications

Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells

Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells

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

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

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