In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

BACKGROUND: Computer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17ß-estradiol metabolite that induces apoptosis in various cancer cell lines including...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Visagie,Michelle Helen, Jaiswal,Seema Rummurat, Joubert,Anna Margaretha
Lenguaje:	English
Publicado:	Sociedad de Biología de Chile 2016
Materias:	Morphology Apoptosis Cervical cancer ESE-15-ol
Acceso en línea:	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602016000100043
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:scielo:S0716-97602016000100043
record_format	dspace
spelling	oai:scielo:S0716-976020160001000432016-12-01In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cellsVisagie,Michelle HelenJaiswal,Seema RummuratJoubert,Anna Margaretha Morphology Apoptosis Cervical cancer ESE-15-ol BACKGROUND: Computer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17ß-estradiol metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple myeloma. Owing to 2ME2's poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2 (1 μM), were assessed on morphology and apoptosis induction in cervical cancer cells. RESULTS: Transmission electron microscopy, scanning electron microscopy and polarization-optical transmitted light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8 activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower pharmacological concentration (180 nM) compared to 2ME2 (1 μM physiological concentration. CONCLUSION: Computer-based technology is essential in drug discovery and together with in vitro studies for the evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro. Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability while preserving apoptotic activity in vitro.info:eu-repo/semantics/openAccessSociedad de Biología de ChileBiological Research v.49 20162016-01-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602016000100043en10.1186/s40659-016-0104-5
institution	Scielo Chile
collection	Scielo Chile
language	English
topic	Morphology Apoptosis Cervical cancer ESE-15-ol
spellingShingle	Morphology Apoptosis Cervical cancer ESE-15-ol Visagie,Michelle Helen Jaiswal,Seema Rummurat Joubert,Anna Margaretha In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
description	BACKGROUND: Computer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17ß-estradiol metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple myeloma. Owing to 2ME2's poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2 (1 μM), were assessed on morphology and apoptosis induction in cervical cancer cells. RESULTS: Transmission electron microscopy, scanning electron microscopy and polarization-optical transmitted light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8 activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower pharmacological concentration (180 nM) compared to 2ME2 (1 μM physiological concentration. CONCLUSION: Computer-based technology is essential in drug discovery and together with in vitro studies for the evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro. Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability while preserving apoptotic activity in vitro.
author	Visagie,Michelle Helen Jaiswal,Seema Rummurat Joubert,Anna Margaretha
author_facet	Visagie,Michelle Helen Jaiswal,Seema Rummurat Joubert,Anna Margaretha
author_sort	Visagie,Michelle Helen
title	In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
title_short	In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
title_full	In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
title_fullStr	In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
title_full_unstemmed	In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
title_sort	in vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
publisher	Sociedad de Biología de Chile
publishDate	2016
url	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602016000100043
work_keys_str_mv	AT visagiemichellehelen invitroassessmentofacomputerdesignedpotentialanticanceragentincervicalcancercells AT jaiswalseemarummurat invitroassessmentofacomputerdesignedpotentialanticanceragentincervicalcancercells AT joubertannamargaretha invitroassessmentofacomputerdesignedpotentialanticanceragentincervicalcancercells
_version_	1718441557806284800

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

Ejemplares similares