Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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3-Deoxysappanchalcone Inhibits Cell Growth of Gefitinib-Resistant Lung Cancer Cells by Simultaneous Targeting of EGFR and MET Kinases

  • Jin-Young Lee (Department of Biological Sciences, Keimyung University) ;
  • Seung-On Lee (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Ah-Won Kwak (Biosystem Research Group, Department of Predictive Toxicology, Korea Institute of Toxicology) ;
  • Seon-Bin Chae (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Seung-Sik Cho (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Goo Yoon (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Ki-Taek Kim (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Yung Hyun Choi (Department of Biochemistry, College of Korean Medicine, Dong-Eui University) ;
  • Mee-Hyun Lee (College of Korean Medicine, Dongshin University) ;
  • Sang Hoon Joo (College of Pharmacy, Daegu Catholic University) ;
  • Jin Woo Park (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Jung-Hyun Shim (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University)
  • Received : 2023.03.29
  • Accepted : 2023.04.18
  • Published : 2023.07.01
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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 anti-cancer mechanisms. 3-DSC could potentially be used as an effective anti-cancer strategy to overcome EGFR and MET target drug-resistant lung cancer.

Keywords

Acknowledgement

This research was funded by the Basic Science Research Program of the National Research Foundation Korea (NRF), grant number 2019R1A2C1005899; an NRF grant funded by the Korean government (MSIT), grant number 2022R1A5A8033794.

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