Jeong, Soyeon Farag, Ahmed Karam Yun, Hye Kyeong Jeong, Yoon A. Kim, Dae Yeong Jo, Min Jee Park, Seong Hye Kim, Bo Ram Kim, Jung Lim Lee, Dae-Hee Roh, Eun Joo Oh, Sang Cheul 2024-01-12T02:43:54Z 2024-01-12T02:43:54Z 2022-03-07 2019-10 1535-7163 https://pubs.kist.re.kr/handle/201004/76324 Multifunctional, antiproliferative small molecules are deemed to offer pharmacodynamic and pharmacokinetic benefits over combination therapy, in addition to reducing toxicity, cancer resistance, and therapy costs. In this study, we conducted an in vitro cellular screen of our recently reported series of EGFR/HER2 inhibitors. Due to its preferentially apoptosis triggering in colorectal cancer (CRC) cells compared to normal colon cells, the compound AF8c was selected for further evaluation. Analysis of the AF8c mode of action in CRC cells revealed that it mediates apoptosis via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as selective activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), but not DR4. 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 mice with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC. Moreover, it could also be a potential starting point for the understanding of the structural features of quinazoline-based ErbB family inhibitors targeting the TRAIL cascade. English American Association for Cancer Research AF8c, a pan-ErbB family inhibitor induces apoptotic cell death by stimulating DR5/Nrf2 via ROS in colorectal cancer cells Conference 10.1158/1535-7163.TARG-19-A111 1 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics US Boston, MA 2019-10-26 Molecular Cancer Therapeutics 000510047200099