dc.contributor.author |
Theron, Anne Elisabeth
|
|
dc.contributor.author |
Nolte, Elsie M.
|
|
dc.contributor.author |
Lafanechere, Laurence
|
|
dc.contributor.author |
Joubert, Annie M.
|
|
dc.date.accessioned |
2014-01-27T08:31:54Z |
|
dc.date.available |
2014-01-27T08:31:54Z |
|
dc.date.issued |
2013-08-27 |
|
dc.description.abstract |
BACKGROUND: 2-Methoxyestradiol has been shown to induce both autophagy and apoptosis in various carcinogenic
cell lines. Although a promising anti-cancer agent, it has poor bioavailability and rapid in vivo metabolism which
decreases its efficiency. In order to improve 2-methoxyestradiol’s anti-proliferative properties, a novel 2-
methoxyestradiol analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5 (10)16-tetraene (ESE-16), was previously in silicodesigned
in our laboratory. This study investigated ESE-16 for its anti-proliferative potential on a cervical
adenocarcinoma cell (HeLa) cell line. Additionally, the possible intracellular crosstalk mechanisms between the two
types of cell death were investigated.
METHODS AND RESULTS: HeLa cells exposed to 0.5 μM ESE-16 for 24 hours showed morphological evidence of both
apoptotic and autophagic death pathways as assessed by polarization-optical transmitted light differential
interference contrast microscopy, fluorescent microscopy and transmission electron microscopy. Flow cytometric
cyclin B1 quantification revealed induction of programmed cell death after halting cell cycle progression in
metaphase. Confocal microscopy demonstrated that ESE-16 caused microtubule fragmentation. Flow cytometric
analysis of cell cycle progression and phosphatidylserine flip determination confirmed induction of apoptosis.
Moreover, an increase in aggresome formation and microtubule-associated protein light chain, LC3, was
demonstrated indicative of autophagy. Both caspase 8 and 3 were upregulated in a spectrophotometric analysis,
indicating the involvement of the extrinsic pathway of apoptotic induction.
CONCLUSIONS: We conclude that the novel in silico-designed compound, ESE-16, exerts its anti-proliferative effect on
the tumorigenic human epithelial cervical (HeLa) cells by sequentially targeting microtubule integrity, resulting in a
metaphase block, causing induction of both autophagic and apoptotic cell death via a crosstalk mechanism that
involves the extrinsic pathway. Future investigations will expand on signal transduction pathways involved in both
apoptosis and autophagy for assessment of ESE-16 effects on microtubule dynamic instability parameters. |
en_US |
dc.description.librarian |
am2014 |
en_US |
dc.description.sponsorship |
The Cancer Association of
South Africa (CANCA) (AOS201), the Medical Research Council (MRC)
(AOS536), the National Research Foundation (NRF) (AOT060), The Research
Committee of the University of Pretoria (RESCOM) (AOR984), South African
Medical Association (SAMA) and the Research Development Programme (UP)
(AOV8410). |
en_US |
dc.description.uri |
http://www.cancerci.com/content/13/1/87 |
en_US |
dc.identifier.citation |
Theron et al.: Molecular crosstalk between apoptosis and autophagy induced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cells. Cancer Cell International 2013 13:87. |
en_US |
dc.identifier.issn |
1475-2867 (print) |
|
dc.identifier.issn |
1475-2867 (online) |
|
dc.identifier.other |
10.1186/1475-2867-13-87 |
|
dc.identifier.uri |
http://hdl.handle.net/2263/33111 |
|
dc.language.iso |
en |
en_US |
dc.publisher |
BioMed Central |
en_US |
dc.rights |
© 2013 Theron et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License |
en_US |
dc.subject |
2-methoxyestradiol |
en_US |
dc.subject |
ESE-16 |
en_US |
dc.subject |
Analogue |
en_US |
dc.subject |
Apoptosis |
en_US |
dc.subject |
Autophagy |
en_US |
dc.subject |
Caspase |
en_US |
dc.subject |
Crosstalk |
en_US |
dc.subject |
Mitotic block |
en_US |
dc.subject |
Microtubules |
en_US |
dc.subject |
2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene |
en_US |
dc.title |
Molecular crosstalk between apoptosis and autophagy induced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cells |
en_US |
dc.type |
Article |
en_US |