Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo.
Yu ZouDi ZhaoChang YanYanpeng JiJin LiuJinyi XuYisheng LaiJide TianYihua ZhangZhangjian HuangPublished in: Journal of medicinal chemistry (2018)
Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive investigation and clinical application. Ligustrazine possesses a water-soluble pyrazine skeleton and can inhibit proliferation and metastasis of cancer cells. We synthesized compound 3 by replacement of the trimethoxyphenyl of 1 with ligustrazine moiety and further introduced 2-Cl, -Br, and -I to 3 for synthesis of 4-6, respectively. Compound 4 possessed 14-fold greater aqueous solubility than 1 and increased ROS levels in colorectal cancer HCT-116 cells. Additionally, 4 preferably inhibited proliferation, migration, invasion, and heteroadhesion of HCT-116 cells. Treatment with 4 suppressed tumor growth and lung metastasis in vivo and prolonged the survival of tumor-bearing mice. Furthermore, 4 mitigated TGF-β1-induced epithelial-mesenchymal transition and Wnt/β-catenin activation by inhibiting the Akt and GSK-3β phosphorylation in HCT-116 cells. Collectively, 4 displayed significant antiproliferation and antimetastasis activities, superior to 1.
Keyphrases
- cell cycle arrest
- signaling pathway
- induced apoptosis
- epithelial mesenchymal transition
- cell death
- pi k akt
- reactive oxygen species
- cell proliferation
- water soluble
- stem cells
- dna damage
- transforming growth factor
- oxidative stress
- endoplasmic reticulum stress
- type diabetes
- metabolic syndrome
- molecular docking
- insulin resistance
- young adults
- drug induced
- protein kinase
- high fat diet induced