AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells
SIMPLE SUMMARY: AF8c, a lapatinib hybrid quinazoline-based EGFR/HER2 inhibitor, was chosen to scrutinize its antiproliferative activity in colorectal cancer (CRC) cells. We found that AF8cinduced apoptosis in CRC cells via diverse mechanisms. In addition to inhibiting the phosphorylation of the ErbB...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264837/ https://www.ncbi.nlm.nih.gov/pubmed/35804815 http://dx.doi.org/10.3390/cancers14133043 |
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author | Jeong, Soyeon Farag, Ahmed K. Yun, Hye Kyeong Jeong, Yoon A. Kim, Dae Yeong Jo, Min Jee Park, Seong Hye Kim, Bo Ram Kim, Jung Lim Kim, Bu Gyeom Lee, Dae-Hee Roh, Eun Joo Oh, Sang Cheul |
author_facet | Jeong, Soyeon Farag, Ahmed K. Yun, Hye Kyeong Jeong, Yoon A. Kim, Dae Yeong Jo, Min Jee Park, Seong Hye Kim, Bo Ram Kim, Jung Lim Kim, Bu Gyeom Lee, Dae-Hee Roh, Eun Joo Oh, Sang Cheul |
author_sort | Jeong, Soyeon |
collection | PubMed |
description | SIMPLE SUMMARY: AF8c, a lapatinib hybrid quinazoline-based EGFR/HER2 inhibitor, was chosen to scrutinize its antiproliferative activity in colorectal cancer (CRC) cells. We found that AF8cinduced apoptosis in CRC cells via diverse mechanisms. In addition to inhibiting the phosphorylation of the ErbB family, AF8c increased the mRNA and protein levels of death receptor 5 (DR5) in vitro and in vivo. In addition, AF8c upregulated several ER stress proteins and the redox-sensitive nuclear respiratory factor 2 alpha subunit (Nrf2) in a p53-dependent manner. We also found that the AF8c-induced increase in the levels of Nrf2, DR5, and apoptosis was diminished by p53 downregulation or knockdown. Furthermore, AF8c showed higher antiproliferative activity than lapatinib in the CRC mouse model in vivo. Therefore, our results suggest AF8c as a highly effective polypharmacological small molecule with an encouraging safety profile, both in vitro and in vivo, for further evaluation as a treatment of CRC. ABSTRACT: Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer (CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC. |
format | Online Article Text |
id | pubmed-9264837 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92648372022-07-09 AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells Jeong, Soyeon Farag, Ahmed K. Yun, Hye Kyeong Jeong, Yoon A. Kim, Dae Yeong Jo, Min Jee Park, Seong Hye Kim, Bo Ram Kim, Jung Lim Kim, Bu Gyeom Lee, Dae-Hee Roh, Eun Joo Oh, Sang Cheul Cancers (Basel) Article SIMPLE SUMMARY: AF8c, a lapatinib hybrid quinazoline-based EGFR/HER2 inhibitor, was chosen to scrutinize its antiproliferative activity in colorectal cancer (CRC) cells. We found that AF8cinduced apoptosis in CRC cells via diverse mechanisms. In addition to inhibiting the phosphorylation of the ErbB family, AF8c increased the mRNA and protein levels of death receptor 5 (DR5) in vitro and in vivo. In addition, AF8c upregulated several ER stress proteins and the redox-sensitive nuclear respiratory factor 2 alpha subunit (Nrf2) in a p53-dependent manner. We also found that the AF8c-induced increase in the levels of Nrf2, DR5, and apoptosis was diminished by p53 downregulation or knockdown. Furthermore, AF8c showed higher antiproliferative activity than lapatinib in the CRC mouse model in vivo. Therefore, our results suggest AF8c as a highly effective polypharmacological small molecule with an encouraging safety profile, both in vitro and in vivo, for further evaluation as a treatment of CRC. ABSTRACT: Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer (CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC. MDPI 2022-06-21 /pmc/articles/PMC9264837/ /pubmed/35804815 http://dx.doi.org/10.3390/cancers14133043 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 Jeong, Soyeon Farag, Ahmed K. Yun, Hye Kyeong Jeong, Yoon A. Kim, Dae Yeong Jo, Min Jee Park, Seong Hye Kim, Bo Ram Kim, Jung Lim Kim, Bu Gyeom Lee, Dae-Hee Roh, Eun Joo Oh, Sang Cheul AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells |
title | AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells |
title_full | AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells |
title_fullStr | AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells |
title_full_unstemmed | AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells |
title_short | AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells |
title_sort | af8c, a multi-kinase inhibitor induces apoptosis by activating dr5/nrf2 via ros in colorectal cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264837/ https://www.ncbi.nlm.nih.gov/pubmed/35804815 http://dx.doi.org/10.3390/cancers14133043 |
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