Signaling pathways of ESE-16, an antimitotic and anticarbonic anhydrase estradiol analog, in breast cancer cells

• Published in: PloS one 2013-01, Vol.8 (1), p.e53853-e53853
• Main Authors: Stander, Barend Andre, Joubert, Fourie, Tu, Chingkuang, Sippel, Katherine H, McKenna, Robert, Joubert, Annie Margaretha
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Antibodies; Antibody microarrays; Anticancer properties; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; Bcl-2 protein; Bioavailability; Biochemistry; Bioinformatics; Biology; Breast cancer; Cancer; Cancer cells; Cancer metastasis; Carbonic anhydrase; Carbonic anhydrase II; Carbonic Anhydrase II - antagonists & inhibitors; Carbonic Anhydrase II - metabolism; Cell cycle; Cell Cycle Checkpoints - drug effects; Clinical trials; Cytometry; Depolarization; DNA microarrays; Estradiol; Estradiol - analogs & derivatives; Estradiol - pharmacology; Female; Flow cytometry; Free radicals; Gene expression; Gene Expression Regulation, Neoplastic; Gene flow; Genes; Genetic research; Humans; Iron; JNK protein; Kinases; Laboratories; MAP Kinase Kinase 4 - metabolism; MCF-7 Cells; Medical research; Medicine; Membrane potential; Metabolism; Metastases; Metastasis; Mitochondria; Oxidative stress; p38 Mitogen-Activated Protein Kinases - metabolism; Phagocytosis; Phenols (Class of compounds); Phosphorylation; Protein arrays; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Research projects; Rodents; Sex hormones; Signal Transduction - drug effects; Signaling; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053853

The aim of this study was to characterize the in vitro action of 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) on non-tumorigenic MCF-12A, tumorigenic MCF-7 and metastatic MDA-MB-231 breast cancer cells. ESE-16 is able to inhibit the activity of a carbonic anhydrase II and a mimic of carbonic anhydrase IX in the nanomolar range. Gene and protein expression studies using various techniques including gene and antibody microarrays and various flow cytometry assays yielded valuable information about the mechanism of action of ESE-16. The JNK pathway was identified as an important pathway mediating the effects of ESE-16 while the p38 stress-induced pathway is more important in MDA-MB-231 cells exposed to ESE-16. Lysosomal rupture and iron metabolism was identified as important mediators of mitochondrial membrane depolarization. Abrogation of Bcl-2 phosphorylation status as a result of ESE-16 also plays a role in inducing mitochondrial membrane depolarization. The study provides a basis for future research projects to develop the newly synthesized compound into a clinically usable anticancer agent either alone or in combination with other agents. Antimitotic, anticarbonic anhydrase IX, apoptosis, autophagy, cell cycle arrest, Bcl-2, JNK, p38, mitochondrial membrane depolarization, flow cytometry, gene expression and protein microarray, anticancer.