Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells
Several studies have shown that the mammalian target of rapamycin (mTOR) inhibitor; everolimus (EV) improves patient survival in several types of cancer. However, the meaningful efficacy of EV as a single agent for the treatment of colorectal cancer (CRC) has failed to be proven in multiple clinical...
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American Chemical Society
2019
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2-s2.0-85066960433 Maki M.A.A.; Kumar P.V.; Cheah S.-C.; Siew Wei Y.; Al-Nema M.; Bayazeid O.; Majeed A.B.B.A. Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells 2019 ACS Omega 4 5 10.1021/acsomega.9b00109 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85066960433&doi=10.1021%2facsomega.9b00109&partnerID=40&md5=4bcb43e34dd07537585b3109737c377c Several studies have shown that the mammalian target of rapamycin (mTOR) inhibitor; everolimus (EV) improves patient survival in several types of cancer. However, the meaningful efficacy of EV as a single agent for the treatment of colorectal cancer (CRC) has failed to be proven in multiple clinical trials. Combination therapy is one of the options that could increase the efficacy and decrease the toxicity of the anticancer therapy. This study revealed that the β-cyclodextrin (β-CD):FGF7 complex has the potential to improve the antiproliferative effect of EV by preventing FGF receptor activation and by enhancing EV cellular uptake and intracellular retention. Molecular docking techniques were used to investigate the possible interaction between EV, β-CD, and FGF7. Molecular docking insights revealed that β-CD and EV are capable to form a stable inclusion complex with FGF at the molecular level. The aqueous solubility of the inclusion complex was increased (3.1 ± 0.23 μM) when compared to the aqueous solubility of pure EV (1.7 ± 0.16 μM). In addition, the in vitro cytotoxic activity of a FGF7:β-CD:EV complex on Caco-2 cell line was investigated using real-time xCELLigence technology. The FGF7:β-CD:EV complex has induced apoptosis of Caco-2 cells and shown higher cytotoxic activity than the parent drug EV. With the multitargets effect of β-CD:FGF7 and EV, the antiproliferative effect of EV was remarkably improved as the IC50 value of EV was reduced from 9.65 ± 1.42 to 1.87 ± 0.33 μM when compared to FGF7:β-CD:EV complex activity. In conclusion, the findings advance the understanding of the biological combinational effects of the β-CD:FGF7 complex and EV as an effective treatment to combat CRC. © 2019 American Chemical Society. American Chemical Society 24701343 English Article All Open Access; Gold Open Access |
author |
Maki M.A.A.; Kumar P.V.; Cheah S.-C.; Siew Wei Y.; Al-Nema M.; Bayazeid O.; Majeed A.B.B.A. |
spellingShingle |
Maki M.A.A.; Kumar P.V.; Cheah S.-C.; Siew Wei Y.; Al-Nema M.; Bayazeid O.; Majeed A.B.B.A. Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells |
author_facet |
Maki M.A.A.; Kumar P.V.; Cheah S.-C.; Siew Wei Y.; Al-Nema M.; Bayazeid O.; Majeed A.B.B.A. |
author_sort |
Maki M.A.A.; Kumar P.V.; Cheah S.-C.; Siew Wei Y.; Al-Nema M.; Bayazeid O.; Majeed A.B.B.A. |
title |
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells |
title_short |
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells |
title_full |
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells |
title_fullStr |
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells |
title_full_unstemmed |
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells |
title_sort |
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells |
publishDate |
2019 |
container_title |
ACS Omega |
container_volume |
4 |
container_issue |
5 |
doi_str_mv |
10.1021/acsomega.9b00109 |
url |
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85066960433&doi=10.1021%2facsomega.9b00109&partnerID=40&md5=4bcb43e34dd07537585b3109737c377c |
description |
Several studies have shown that the mammalian target of rapamycin (mTOR) inhibitor; everolimus (EV) improves patient survival in several types of cancer. However, the meaningful efficacy of EV as a single agent for the treatment of colorectal cancer (CRC) has failed to be proven in multiple clinical trials. Combination therapy is one of the options that could increase the efficacy and decrease the toxicity of the anticancer therapy. This study revealed that the β-cyclodextrin (β-CD):FGF7 complex has the potential to improve the antiproliferative effect of EV by preventing FGF receptor activation and by enhancing EV cellular uptake and intracellular retention. Molecular docking techniques were used to investigate the possible interaction between EV, β-CD, and FGF7. Molecular docking insights revealed that β-CD and EV are capable to form a stable inclusion complex with FGF at the molecular level. The aqueous solubility of the inclusion complex was increased (3.1 ± 0.23 μM) when compared to the aqueous solubility of pure EV (1.7 ± 0.16 μM). In addition, the in vitro cytotoxic activity of a FGF7:β-CD:EV complex on Caco-2 cell line was investigated using real-time xCELLigence technology. The FGF7:β-CD:EV complex has induced apoptosis of Caco-2 cells and shown higher cytotoxic activity than the parent drug EV. With the multitargets effect of β-CD:FGF7 and EV, the antiproliferative effect of EV was remarkably improved as the IC50 value of EV was reduced from 9.65 ± 1.42 to 1.87 ± 0.33 μM when compared to FGF7:β-CD:EV complex activity. In conclusion, the findings advance the understanding of the biological combinational effects of the β-CD:FGF7 complex and EV as an effective treatment to combat CRC. © 2019 American Chemical Society. |
publisher |
American Chemical Society |
issn |
24701343 |
language |
English |
format |
Article |
accesstype |
All Open Access; Gold Open Access |
record_format |
scopus |
collection |
Scopus |
_version_ |
1809677904826597376 |