DOI QR코드

DOI QR Code

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

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.

References

  1. Byeon, H. K., Ku, M. and Yang, J. (2019) Beyond EGFR inhibition: multilateral combat strategies to stop the progression of head and neck cancer. Exp. Mol. Med. 51, 1-14. https://doi.org/10.1038/s12276-018-0202-2
  2. Elamin, Y. Y., Robichaux, J. P., Carter, B. W., Altan, M., Tran, H., Gibbons, D. L., Heeke, S., Fossella, F. V., Lam, V. K., Le, X., Negrao, M. V., Nilsson, M. B., Patel, A., Vijayan, R. S. K., Cross, J. B., Zhang, J., Byers, L. A., Lu, C., Cascone, T., Feng, L., Luthra, R., San Lucas, F. A., Mantha, G., Routbort, M., Blumenschein, G., Jr., Tsao, A. S. and Heymach, J. V. (2022) Poziotinib for EGFR exon 20-mutant NSCLC: clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. Cancer Cell 40, 754-767.e6. https://doi.org/10.1016/j.ccell.2022.06.006
  3. Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C. M., Zhao, X., Christensen, J., Kosaka, T., Holmes, A. J., Rogers, A. M., Cappuzzo, F., Mok, T., Lee, C., Johnson, B. E., Cantley, L. C. and Janne, P. A. (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039-1043. https://doi.org/10.1126/science.1141478
  4. Fu, X., Zhao, R., Yoon, G., Shim, J. H., Choi, B. Y., Yin, F., Xu, B., Laster, K. V., Liu, K., Dong, Z. and Lee, M. H. (2021) 3-Deoxysappanchalcone inhibits skin cancer proliferation by regulating T-lymphokine-activated killer cell-originated protein kinase in vitro and in vivo. Front. Cell Dev. Biol. 9, 638174.
  5. Huang, C. Y., Hsu, L. H., Chen, C. Y., Chang, G. C., Chang, H. W., Hung, Y. M., Liu, K. J. and Kao, S. H. (2020) Inhibition of alternative cancer cell metabolism of EGFR mutated non-small cell lung cancer serves as a potential therapeutic strategy. Cancers (Basel) 12, 181.
  6. Juchum, M., Gunther, M. and Laufer, S. A. (2015) Fighting cancer drug resistance: opportunities and challenges for mutation-specific EGFR inhibitors. Drug Resist. Updat. 20, 12-28. https://doi.org/10.1016/j.drup.2015.05.002
  7. Kim, J. H., Choo, Y. Y., Tae, N., Min, B. S. and Lee, J. H. (2014) The anti-inflammatory effect of 3-deoxysappanchalcone is mediated by inducing heme oxygenase-1 via activating the AKT/mTOR pathway in murine macrophages. Int. Immunopharmacol. 22, 420-426. https://doi.org/10.1016/j.intimp.2014.07.025
  8. Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J. and Bolton, E. E. (2023) PubChem 2023 update. Nucleic Acids Res. 51, D1373-D1380. https://doi.org/10.1093/nar/gkac956
  9. Kwak, A. W., Lee, M. J., Lee, M. H., Yoon, G., Cho, S. S., Chae, J. I. and Shim, J. H. (2021) The 3-deoxysappanchalcone induces ROS-mediated apoptosis and cell cycle arrest via JNK/p38 MAPKs signaling pathway in human esophageal cancer cells. Phytomedicine 86, 153564.
  10. Lo, H. W. and Hung, M. C. (2007) Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br. J. Cancer 96 Suppl, R16-R20.
  11. McDermott, U., Pusapati, R. V., Christensen, J. G., Gray, N. S. and Settleman, J. (2010) Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. Cancer Res. 70, 1625-1634. https://doi.org/10.1158/0008-5472.CAN-09-3620
  12. Morgillo, F., Della Corte, C. M., Fasano, M. and Ciardiello, F. (2016) Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open 1, e000060.
  13. Perillo, B., Di Donato, M., Pezone, A., Di Zazzo, E., Giovannelli, P., Galasso, G., Castoria, G. and Migliaccio, A. (2020) ROS in cancer therapy: the bright side of the moon. Exp. Mol. Med. 52, 192-203. https://doi.org/10.1038/s12276-020-0384-2
  14. Puri, N. and Salgia, R. (2008) Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer. J. Carcinog. 7, 9.
  15. Rasband, W. S. (1997-2018) ImageJ. U. S. National Institutes of Health, Bethesda, Maryland, USA. Available from: https://imagej.nih.gov/ij/.
  16. Remon, J., Moran, T., Majem, M., Reguart, N., Dalmau, E., Marquez-Medina, D. and Lianes, P. (2014) Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: a new era begins. Cancer Treat. Rev. 40, 93-101. https://doi.org/10.1016/j.ctrv.2013.06.002
  17. Siegel, R. L., Miller, K. D. and Jemal, A. (2017) Cancer statistics, 2017. CA Cancer J. Clin. 67, 7-30. https://doi.org/10.3322/caac.21387
  18. Tartarone, A. and Lerose, R. (2015) Clinical approaches to treat patients with non-small cell lung cancer and epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance. Ther. Adv. Respir. Dis. 9, 242-250. https://doi.org/10.1177/1753465815587820
  19. Trott, O. and Olson, A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-461. https://doi.org/10.1002/jcc.21334
  20. Wang, X., Zhang, H. and Chen, X. (2019) Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2, 141-160. https://doi.org/10.20517/cdr.2019.10
  21. Westover, D., Zugazagoitia, J., Cho, B. C., Lovly, C. M. and Paz-Ares, L. (2018) Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann. Oncol. 29, i10-i19. https://doi.org/10.1093/annonc/mdx703
  22. Yang, J. J., Fang, J., Shu, Y. Q., Chang, J. H., Chen, G. Y., He, J. X., Li, W., Liu, X. Q., Yang, N., Zhou, C., Huang, J. A., Frigault, M. M., Hartmaier, R., Ahmed, G. F., Egile, C., Morgan, S., Verheijen, R. B., Mellemgaard, A., Yang, L. and Wu, Y. L. (2021) A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer. Invest. New Drugs 39, 477-487. https://doi.org/10.1007/s10637-020-01010-4
  23. Yang, Y., Karakhanova, S., Hartwig, W., D'Haese, J. G., Philippov, P. P., Werner, J. and Bazhin, A. V. (2016) Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy. J. Cell. Physiol. 231, 2570-2581. https://doi.org/10.1002/jcp.25349