AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cellsopen access
- Authors
- 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
- Issue Date
- Jul-2022
- Publisher
- Multidisciplinary Digital Publishing Institute (MDPI)
- Keywords
- AF8c; colorectal cancer (CRC); apoptosis; death receptors (DRs); ER stress; reactive oxygen species (ROS); nuclear respiratory factor 2 alpha subunit (Nrf2); kinase; polypharmacological molecules
- Citation
- Cancers, v.14, no.13
- Indexed
- SCIE
SCOPUS
- Journal Title
- Cancers
- Volume
- 14
- Number
- 13
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/61211
- DOI
- 10.3390/cancers14133043
- ISSN
- 2072-6694
2072-6694
- 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.
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- Appears in
Collections - 2. Clinical Science > Department of Medical Oncology and Hematology > 1. Journal Articles
- 4. Research institute > Institute of Convergence New Drug Development > 1. Journal Articles
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