Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2023.070
3-Deoxysappanchalcone Inhibits Cell Growth of Gefitinib-Resistant Lung Cancer Cells by Simultaneous Targeting of EGFR and MET Kinases
Jin-Young Lee1,†, Seung-On Lee2,†, Ah-Won Kwak3, Seon-Bin Chae4, Seung-Sik Cho2,4, Goo Yoon4, Ki-Taek Kim2,4, Yung Hyun Choi5, Mee-Hyun Lee6, Sang Hoon Joo7, Jin Woo Park2,4,* and Jung-Hyun Shim2,4,8,*
1Department of Biological Sciences, Keimyung University, Daegu 42601,
2Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Muan 58554,
3Biosystem Research Group, Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114,
4Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554,
5Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227,
6College of Korean Medicine, Dongshin University, Naju 58245,
7College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea
8The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
*E-mail: s1004jh@gmail.com (Shim JH), jwpark@mokpo.ac.kr (Park JW)
Tel: +82-61-450-2684 (Shim JH), +82-61-450-2704 (Park JW)
Fax: +82-61-450-2689 (Shim JH), +82-61-450-2689 (Park JW)
†The first two authors contributed equally to this work.
Received: March 29, 2023; Revised: April 9, 2023; Accepted: April 18, 2023; Published online: May 16, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The mechanistic functions of 3-deoxysappanchalcone (3-DSC), a chalcone compound known to have many pharmacological effects on lung cancer, have not yet been elucidated. In this study, we identified the comprehensive anti-cancer mechanism of 3-DSC, which targets EGFR and MET kinase in drug-resistant lung cancer cells. 3-DSC directly targets both EGFR and MET, thereby inhibiting the growth of drug-resistant lung cancer cells. Mechanistically, 3-DSC induced cell cycle arrest by modulating cell cycle regulatory proteins, including cyclin B1, cdc2, and p27. In addition, concomitant EGFR downstream signaling proteins such as MET, AKT, and ERK were affected by 3-DSC and contributed to the inhibition of cancer cell growth. Furthermore, our results show that 3-DSC increased redox homeostasis disruption, ER stress, mitochondrial depolarization, and caspase activation in gefitinib-resistant lung cancer cells, thereby abrogating cancer cell growth. 3-DSC induced apoptotic cell death which is regulated by Mcl-1, Bax, Apaf-1, and PARP in gefitinib-resistant lung cancer cells. 3-DSC also initiated the activation of caspases, and the pan-caspase inhibitor, Z-VAD-FMK, abrogated 3-DSC induced-apoptosis in lung cancer cells. These data imply that 3-DSC mainly increased mitochondria-associated intrinsic apoptosis in lung cancer cells to reduce lung cancer cell growth. Overall, 3-DSC inhibited the growth of drug-resistant lung cancer cells by simultaneously targeting EGFR and MET, which exerted anti-cancer effects through cell cycle arrest, mitochondrial homeostasis collapse, and increased ROS generation, eventually triggering anticancer mechanisms. 3-DSC could potentially be used as an effective anti-cancer strategy to overcome EGFR and MET target drug-resistant lung cancer.
Keywords: 3-Deoxysappanchalcone, Human lung adenocarcinoma cells, Gefitinib, Resistance

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