Drug Design, Development and Therapy (May 2024)

A Novel Tetramethylpyrazine Chalcone Hybrid- HCTMPPK, as a Potential Anti-Lung Cancer Agent by Downregulating MELK

  • Ma Y,
  • Cui Q,
  • Zhu W,
  • Wang M,
  • Zhai L,
  • Hu W,
  • Liu D,
  • Liu M,
  • Li Y,
  • Li M,
  • Han W

Journal volume & issue
Vol. Volume 18
pp. 1531 – 1546

Abstract

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Yan Ma,1,2,* Qian Cui,3,* Wenjing Zhu,1,4,* Mei Wang,1,2 Li Zhai,5 Wenmin Hu,1,2 Dongdong Liu,6 Min Liu,5 Yongchun Li,2 Meng Li,2 Wei Han1,2 1Qingdao Key Laboratory of Common Diseases, Qingdao Municipal Hospital, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 260071, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Shenzhen Luohu People’s Hospital, Shenzhen, 518000, People’s Republic of China; 4NMPA Key Laboratory for Quality Research and Evaluation of Traditional Marine Chinese Medicine, Qingdao, 266071, People’s Republic of China; 5Department of Pharmacy, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Shanting District People’s Hospital, Zaozhuang, 277200, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Han; Meng Li, Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266071, People’s Republic of China, Email [email protected]; [email protected]: Lung adenocarcinoma currently ranks the leading causes of cancer-related mortality worldwide. Many anti-inflammation herbs, like tetramethylpyrazine, have shown their anti-tumor potentials. Here, we evaluated the role of a novel chalcone derivative of tetramethylpyrazine ((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1, HCTMPPK) in lung adenocarcinoma.Methods: The effects of HCTMPPK on cell proliferation, apoptosis, and invasion were investigated by in-vitro assays, including CCK-8, colony formation assay, flow cytometry, transwell assay, and wound-healing assay. The therapeutic potential of HCTMPPK in vivo was evaluated in xenograft mice. To figure out the target molecules of HCTMPPK, a network pharmacology approach and molecular docking studies were employed, and subsequent experiments were conducted to confirm these candidate molecules.Results: HCTMPPK effectively suppressed the proliferative activity and migration, as well as enhanced the apoptosis of A549 cells in a concentration-dependent manner. Consistent with this, tumor growth was inhibited by HCTMPPK significantly in vivo. Regarding the mechanisms, HCTMPPK down-regulated Bcl-2 and MMP-9 and up-regulating Bax and cleaved-caspase-3. Subsequently, we identified 601 overlapping DEGs from LUAD patients in TCGA and GEO database. Then, 15 hub genes were identified by PPI network and CytoHubba. Finally, MELK was verified to be the HCTMPPK targeted site, through the molecular docking studies and validation experiments.Conclusion: Overall, our study indicates HCTMPPK as a potential MELK inhibitor and may be a promising candidate for the therapy of lung cancer.Keywords: HCTMPPK((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1), chalcone, TMP, lung adenocarcinoma, network pharmacology, AutoDock

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