title: Paeoniflorin inhibits macrophage-mediated lung cancer metastasis.
abstract: Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages (M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages (stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 or P < 0.05 vs control group). Paeoniflorin could decrease the cell populations at S phases (paeoniflorin 10, 30, 100 μmol·L(-1), P < 0.05 vs control group) and increase the cell populations at G0-G1 phases of Lewis lung cancer cells (paeoniflorin 100 μmol·L(-1), P < 0.05 vs control group) and reduce the numbers of M2 macrophages in peritoneal macrophages induced by IL-4 (paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 vs Control group). Paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo (paeoniflorin 20, 40 mg·kg(-1), P < 0.01 vs control group). These results suggest that paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft partly through inhibiting the alternative activation of macrophages.
authors.affiliation: State Key Laboratory of Natural Medicines, Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing 211198, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China. Electronic address: chengangling@cpu.edu.cn.
authors.forename: Gang-Ling
authors.initials: GL
authors.lastname: Chen
authors.affiliation: Murad Research Institute for Modernized Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, China.
authors.forename: Fang-Zhen
authors.initials: FZ
authors.lastname: Lin
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005960:Glucosides / Q000008:administration & dosage*; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D039821:Monoterpenes / Q000008:administration & dosage*; D009362:Neoplasm Metastasis; D029596:Paeonia / Q000737:chemistry*; D006027:Glycosides
chemical_list: D005960:Glucosides; D015847:Interleukin-4; D039821:Monoterpenes; C015423:peoniflorin; D006027:Glycosides
keywords: Alternatively activated macrophages; Lung cancer; Metastasis; Paeoniflorin; Tumor-associated macrophages