In Vitro Evaluation of ESE-15-ol, an Estradiol Analogue with Nanomolar Antimitotic and Carbonic Anhydrase Inhibitory Activity

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

doi:10.1371/journal.pone.0052205

Cited by 27 publications

(71 citation statements)

References 41 publications

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“…Carbonic anhydrases are zinc enzymes that control the CO 2 /bicarbonate ratio in the blood, and thus control the acid/base balance in the body [10,[24][25][26]. CAIX is overexpressed in a variety of tumors and contributes to the acidification of the extracellular environment of the tumors due to the conversion of carbon dioxide and water to carbonic acid [24,27,28]. The acidic environment promotes the expression of proteinases contributing to tumor growth, survival and metastasis [24,27,28].…”

Section: Introductionmentioning

confidence: 99%

“…CAIX is overexpressed in a variety of tumors and contributes to the acidification of the extracellular environment of the tumors due to the conversion of carbon dioxide and water to carbonic acid [24,27,28]. The acidic environment promotes the expression of proteinases contributing to tumor growth, survival and metastasis [24,27,28]. A comparison of the chemical structures of ESE-16 and 2ME reveals an exchange of a sulfamoylated group for a hydroxyl group at position 3 and the removal of a hydroxyl group at position 17 on ESE-16 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Sulfamoylation of 2ME is suggested to increase bioavailability, since these analogues are able to journey through the liver without undergoing presystemic metabolism [8,10,22,30]. The latter characteristic is due to the ability of sulfamoylated derivatives to reversibly bind to the carbonic anhydrase II (CAII) found in erythrocytes [10,31] causing the slow release of the compound into the blood stream, allowing the compound to bypass presystemic metabolism [10,28,31]. Fig.…”

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: 99%

Section: Introductionmentioning

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

Self Cite

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“…CAIX contributes to the acidic extracellular environment associated with tumors, which in turn promotes the expression of proteinases that contribute to invasion and metastasis. This compound also reversibly binds to CAII in red blood cells in order to bypass the first-pass metabolism in the liver owing to release into the blood stream from CAII, resulting in increased bioavailability (Stander et al, 2012). This could explain why the compounds do not affect platelets.…”

Section: Discussionmentioning

confidence: 99%

Ex vivoDetermination of an Estradiol Analogue-Induced Changes on Platelet Morphology and Angiogenic Biomarkers

2015

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Angiogenesis is a closely controlled biological process that takes place during fetal development of blood vessels and wound healing, and includes the development of new blood vessels from preexisting blood vessels. Tumor angiogenesis is a means by which tumors obtain oxygen, nutrition and promote tumor growth. Angiogenesis-regulating proteins are therefore ideal biomarkers in the study of tumor pathophysiology. In our laboratory, a new in silico-designed analogue of 2-methoxyestradiol has been synthesized with angiogenic properties, namely 2-ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16). The ex vivo influence of ESE-16 on angiogenesis and morphology in platelets of healthy participants was investigated. Scanning electron microscopy revealed no morphological changes in ESE-16-treated platelets. The possible antiangiogenic effect of ESE-16-exposed platelets was determined by means of flow cytometry measurement of angiogenic protein levels, which were significantly increased after platelets were added to tumorigenic breast epithelial cells. This indicates that binding of platelets to cancer cells causes differential release of platelet constituents. Vascular endothelial growth factor levels were decreased in platelets, whereas platelet-derived growth factor and matrix metallopeptidase-9 levels were not significantly affected in platelets. In light of the above-mentioned data, further investigation of ESE-16's influence on morphology and angiogenic markers in platelets of cancer patients is warranted.

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“…Nuclei were stained with 4',6-diamidino-2-phenylindole (DAPI, Sigma) afterwards for 10 min. Stained cells were mounted on microscopy slides and viewed with a Zeiss 510 META confocal laser microscope (Carl Zeiss MicroImaging GmbH, Göttingen, Germany) [30]. …”

Section: Methodsmentioning

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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In Vitro Evaluation of ESE-15-ol, an Estradiol Analogue with Nanomolar Antimitotic and Carbonic Anhydrase Inhibitory Activity

Cited by 27 publications

References 41 publications

Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells

Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells

Ex vivoDetermination of an Estradiol Analogue-Induced Changes on Platelet Morphology and Angiogenic Biomarkers

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

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