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-O-sulfamoylestra-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-ID autophagy detection kit and the aggresome detection assay. Results showed an increase in autophagic vacuole and aggresome formation in ESE-16 treated cells, confirming the induction of cell death via autophagy. Cell cycle progression demonstrated an increase in the sub-G1 fraction (indicative of the presence of apoptosis). 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.
Highlights
Esophageal cancer (EC) is the eighth most common incident cancer in the world and due to its high fatality rate, it ranks sixth among all cancers in terms of mortality [1,2,3]
Qualitative data reveal a decrease in cell density and cell death via apoptosis and autophagy polarization-optical transmitted light differential interference contrast microscopy (PlasDIC) was used to visualize the effect that 0.18 μM of ESE-16 has on SNO cell morphology after 24 h of exposure
Cells treated with ESE-16 (Fig. 2D) showed a decrease in cell density, the occurrence of membrane blebbing, and the presence of apoptotic bodies when compared to the relevant controls (Fig. 2A–C)
Summary
Esophageal cancer (EC) is the eighth most common incident cancer in the world and due to its high fatality rate, it ranks sixth among all cancers in terms of mortality [1,2,3]. One of the main reasons for the high incidence rates in these areas is believed to be the presence of the mycotoxin fumonisin B1 (FB1). One of the best-known characteristics of cancer cells is their rapid and uncontrolled division. 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 [7]. Clinical success with several vinca alkaloids and taxanes on a wide variety of human cancers has proven the effectiveness of microtubule-targeting drugs and has prompted a worldwide search for compounds with similar mechanisms [7]. It has low bioavailability due to rapid metabolic degradation by the enzyme 17β-hydroxysteroid dehydrogenase
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