Cargando…

Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach

Colorectal cancer therapies have produced promising clinical responses, but tumor cells rapidly develop resistance to these drugs. It has been previously shown that EC19 and EC23, two EC-synthetic retinoids, have single-agent preclinical anticancer activity in colorectal carcinoma. Here, isobologram...

Descripción completa

Detalles Bibliográficos
Autores principales: Abdelaal, Mohamed R., Ibrahim, Esraa, Elnagar, Mohamed R., Soror, Sameh H., Haffez, Hesham
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409216/
https://www.ncbi.nlm.nih.gov/pubmed/36012706
http://dx.doi.org/10.3390/ijms23169442
_version_ 1784774796652838912
author Abdelaal, Mohamed R.
Ibrahim, Esraa
Elnagar, Mohamed R.
Soror, Sameh H.
Haffez, Hesham
author_facet Abdelaal, Mohamed R.
Ibrahim, Esraa
Elnagar, Mohamed R.
Soror, Sameh H.
Haffez, Hesham
author_sort Abdelaal, Mohamed R.
collection PubMed
description Colorectal cancer therapies have produced promising clinical responses, but tumor cells rapidly develop resistance to these drugs. It has been previously shown that EC19 and EC23, two EC-synthetic retinoids, have single-agent preclinical anticancer activity in colorectal carcinoma. Here, isobologram analysis revealed that they have synergistic cytotoxicity with retinoic acid receptor (RAR) isoform-selective agonistic retinoids such as AC261066 (RARβ2-selective agonist) and CD437 (RARγ-selective agonist) in Caco-2 cells. This synergism was confirmed by calculating the combination index (lower than 1) and the dose reduction index (higher than 1). Flow cytometry of combinatorial IC(50) (the concentration causing 50% cell death) confirmed the cell cycle arrest at the SubG(0)-G(1) phase with potentiated apoptotic and necrotic effects. The reported synergistic anticancer activity can be attributed to their ability to reduce the expression of ATP-binding cassette (ABC) transporters including P-glycoprotein (P-gp1), breast cancer resistance protein (BCRP) and multi-drug resistance-associated protein-1 (MRP1) and Heat Shock Protein 70 (Hsp70). This adds up to the apoptosis-promoting activity of EC19 and EC23, as shown by the increased Caspase-3/7 activities and DNA fragmentation leading to DNA double-strand breaks. This study sheds the light on the possible use of EC-synthetic retinoids in the rescue of multi-drug resistance in colorectal cancer using Caco-2 as a model and suggests new promising combinations between different synthetic retinoids. The current in vitro results pave the way for future studies on these compounds as possible cures for colorectal carcinoma.
format Online
Article
Text
id pubmed-9409216
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-94092162022-08-26 Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach Abdelaal, Mohamed R. Ibrahim, Esraa Elnagar, Mohamed R. Soror, Sameh H. Haffez, Hesham Int J Mol Sci Article Colorectal cancer therapies have produced promising clinical responses, but tumor cells rapidly develop resistance to these drugs. It has been previously shown that EC19 and EC23, two EC-synthetic retinoids, have single-agent preclinical anticancer activity in colorectal carcinoma. Here, isobologram analysis revealed that they have synergistic cytotoxicity with retinoic acid receptor (RAR) isoform-selective agonistic retinoids such as AC261066 (RARβ2-selective agonist) and CD437 (RARγ-selective agonist) in Caco-2 cells. This synergism was confirmed by calculating the combination index (lower than 1) and the dose reduction index (higher than 1). Flow cytometry of combinatorial IC(50) (the concentration causing 50% cell death) confirmed the cell cycle arrest at the SubG(0)-G(1) phase with potentiated apoptotic and necrotic effects. The reported synergistic anticancer activity can be attributed to their ability to reduce the expression of ATP-binding cassette (ABC) transporters including P-glycoprotein (P-gp1), breast cancer resistance protein (BCRP) and multi-drug resistance-associated protein-1 (MRP1) and Heat Shock Protein 70 (Hsp70). This adds up to the apoptosis-promoting activity of EC19 and EC23, as shown by the increased Caspase-3/7 activities and DNA fragmentation leading to DNA double-strand breaks. This study sheds the light on the possible use of EC-synthetic retinoids in the rescue of multi-drug resistance in colorectal cancer using Caco-2 as a model and suggests new promising combinations between different synthetic retinoids. The current in vitro results pave the way for future studies on these compounds as possible cures for colorectal carcinoma. MDPI 2022-08-21 /pmc/articles/PMC9409216/ /pubmed/36012706 http://dx.doi.org/10.3390/ijms23169442 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Abdelaal, Mohamed R.
Ibrahim, Esraa
Elnagar, Mohamed R.
Soror, Sameh H.
Haffez, Hesham
Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach
title Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach
title_full Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach
title_fullStr Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach
title_full_unstemmed Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach
title_short Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach
title_sort augmented therapeutic potential of ec-synthetic retinoids in caco-2 cancer cells using an in vitro approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409216/
https://www.ncbi.nlm.nih.gov/pubmed/36012706
http://dx.doi.org/10.3390/ijms23169442
work_keys_str_mv AT abdelaalmohamedr augmentedtherapeuticpotentialofecsyntheticretinoidsincaco2cancercellsusinganinvitroapproach
AT ibrahimesraa augmentedtherapeuticpotentialofecsyntheticretinoidsincaco2cancercellsusinganinvitroapproach
AT elnagarmohamedr augmentedtherapeuticpotentialofecsyntheticretinoidsincaco2cancercellsusinganinvitroapproach
AT sororsamehh augmentedtherapeuticpotentialofecsyntheticretinoidsincaco2cancercellsusinganinvitroapproach
AT haffezhesham augmentedtherapeuticpotentialofecsyntheticretinoidsincaco2cancercellsusinganinvitroapproach