Abstract
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.Keywords: Antimitotic, anticarbonic anhydrase IX, apoptosis, autophagy, cell cycle arrest, Bcl-2, JNK, p38, mitochondrial membrane depolarization, flow cytometry, gene expression and protein microarray, anticancer.
Highlights
Antimitotic compounds that interfere with the microtubule dynamics in actively dividing cells remain a viable strategy for developing new anticancer agents as evidenced by recent patent applications [1]
In vitro Carbonic Anhydrase Inhibition ESE-16 was synthesized as a carbonic anhydrase IX (CAIX) inhibitor that can selectively inhibit the development of metastatic processes due extracellular acidification by CAIX
Kinetics data indicated that ESE-16 inhibited the CAIX mimic (Ki = 453643 nM) at a lower concentration when compared to the wild-type CAII (Ki = 569661 nM) (Figure 1A)
Summary
Antimitotic compounds that interfere with the microtubule dynamics in actively dividing cells remain a viable strategy for developing new anticancer agents as evidenced by recent patent applications [1]. Improved oral bioavailability is argued to be as a result of the potential of aryl sulphamoyl containing compounds to reversibly bind to carbonic anhydrase II present in red blood cells and in turn circumvent first pass liver metabolism [4]. ESE-16 was synthesized due to its potential antimitotic as well as carbonic anhydrase IX (CAIX) inhibitory activity. CAIX, an extracellular carbonic anhydrase isoenzyme, is over expressed in a variety of tumors and contributes to the acidification of the extracellular microenvironment by catalyzing the conversion of carbon dioxide and water to carbonic acid [4,13]. Selective inhibition of CAIX provides a valuable strategy for curtailing the development of metastatic processes associated with acidic microenvironmental conditions in tumors
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