title: Matrine derivative WM130 inhibits hepatocellular carcinoma by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways.
abstract: Matrine, a sophora alkaloid, has been demonstrated to exert antitumor effects on many types of cancer. However, its bioactivity is weak and its potential druggability is low. We modified the structure of matrine and obtained a new matrine derivative, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities than matrine. In this study, we investigated the antitumor activity and the underlying mechanisms of WM130 on hepatocellular carcinoma (HCC) cells in vitro and in vivo, and found that WM130 inhibited the proliferation, invasion, migration and induced apoptosis of HCC cells in a dose-dependent manner. Furthermore, after treatment with WM130, the expressions of p-EGFR, p-ERK, p-AKT, MMP-2 and the ratio of Bcl-2/Bax were significantly down-regulated, whereas the expression of PTEN was increased in HCC cells. Moreover, WM130 inhibited Huh-7 xenograft tumor growth in a dose-dependent manner after intravenous administration. Immunohistochemistry results demonstrated that WM130 treatment resulted in down-regulation of p-EGFR, MMP-2, and Ki67 and up-regulation of PTEN. The findings indicated that WM130 could inhibit cell proliferation, invasion, migration and induced apoptosis in HCC cells by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways and may be a novel effective candidate for HCC treatment.
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou 215200, China; Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou 215200, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Weidan
authors.initials: W
authors.lastname: Ji
authors.affiliation: Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qiuye
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Deparment of Cardiothoracic Surgery, No. 105 Hospital of PLA, Hefei 230031, China.
authors.forename: Yongjing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou 215200, China. Electronic address: wjyygqg@sohu.com.
authors.forename: Quangen
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China. Electronic address: suchangqing@gmail.com.
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011807:Quinolizines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D011807:Quinolizines; C000602836:WM130 compound; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Apoptosis; Hepatocellular carcinoma; Matrine derivative; Signaling; Therapeutic effect