title: Anti-tumor enhancement of Fei-Liu-Ping ointment in combination with celecoxib via cyclooxygenase-2-mediated lung metastatic inflammatory microenvironment in Lewis lung carcinoma xenograft mouse model.
abstract: BACKGROUND
  Fei-Liu-Ping (FLP) ointment is an oral prescription medication that has been widely applied to treat lung cancer patients in China. Regulation of the metastatic microenvironment is an important therapeutic approach for prevention and treatment of tumor recurrence and metastasis. The advantage of Traditional Chinese Medicine management of lung cancer lies in the prevention of recurrence and metastasis. Our previous study has demonstrated that FLP ointment could regulate lung inflammatory microenvironment in vitro. However, the effects of FLP on the tumor microenvironment in vivo are still poorly understood. The objective of this study is to investigate the effect of FLP alone or in combination with celecoxib in the prevention of lung cancer progression by Cyclooxygenase (Cox)-2 mediated tumor inflammatory microenvironment in vivo.
  
  
  METHODS
  120 Lewis lung carcinoma xenograft mice were divided equally into four groups: vehicle, FLP, celecoxib, and FLP plus celecoxib. The dynamic growth of the xenografted tumors was observed using an in vivo fluorescence imaging system. Mice were sacrificed on day 14, day 21, and day 28, and tumor specimens and lung tissues were harvested to detect the metastasis-associated protein expression.
  
  
  RESULTS
  Tumor inhibition rate was 15.4, 44.2, 47.4 % at day 14, 37.3, 34.7, 61.5 % at day 21, and 15.5, 10.3, 32.5 % at day 28 after treatment of FLP, celecoxib, and FLP plus celecoxib, respectively. Upon treatment of FLP and celecoxib together, lung metastasis rate was 30 % (8 metastatic nodules) lower than other groups. FLP inhibited Cox-2 expression in a time-dependent manner. Moreover, FLP inhibited N-cadherin, matrix metalloproteinases (MMP)-9, and Vimentin expression. Treatment of FLP in combination with celecoxib was more effective than FLP or celecoxib alone in inhibiting vascular endothelial growth factor, platelet-derived growth factor receptors β, microsomal Prostaglandin E synthase-1, MMP-2, MMP-9, N-cadherin, and Vimentin expression, but increased E-cadherin expression.
  
  
  CONCLUSIONS
  FLP inhibited tumor growth and metastasis in a Lewis lung xenograft mice model through the Cox-2 pathway. FLP in combination with celecoxib enhanced the antitumor growth and anti-metastasis effects. Traditional Chinese herbs combined with anti-inflammatory drugs might offer a promising strategy to prevent tumor metastasis.
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. drliur@126.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. drliur@126.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. macrogone@126.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. macrogone@126.com.
authors.forename: Honggang
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. liweidongdoctor@gmail.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. liweidongdoctor@gmail.com.
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. m2928@126.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. m2928@126.com.|Beijing University of Chinese Medicine, Beijing, 100029, China. m2928@126.com.
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. 908428858@qq.com.|Beijing University of Chinese Medicine, Beijing, 100029, China. 908428858@qq.com.
authors.forename: Shulin
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. hrskyshr@yahoo.co.jp.|Department of Japanese-Oriental (Kampo) Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. hrskyshr@yahoo.co.jp.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Hirasaki
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. houwei1964@sohu.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. houwei1964@sohu.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. huabaojin@sohu.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. huabaojin@sohu.com.
authors.forename: Baojin
authors.initials: B
authors.lastname: Hua
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. liconghuang@163.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. liconghuang@163.com.
authors.forename: Conghuang
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. baoyanju@126.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. baoyanju@126.com.
authors.forename: Yanju
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. booperfect@163.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. booperfect@163.com.|Beijing University of Chinese Medicine, Beijing, 100029, China. booperfect@163.com.
authors.forename: Yebo
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. qixin_2014@126.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. qixin_2014@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. pxr28@sohu.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. pxr28@sohu.com.
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Number 5 Beixiange, Xicheng District, Beijing, 100053, China. zy0214@126.com.|Cancer Institute, China Academy of Chinese Medical Sciences, Beijing, 100053, China. zy0214@126.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D000068579:Celecoxib / Q000008:administration & dosage / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000627:therapeutic use*; D064593:Heterografts; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009824:Ointments; D059016:Tumor Microenvironment
chemical_list: D004365:Drugs, Chinese Herbal; D009824:Ointments; C000597256:fei-liu-ping; D051546:Cyclooxygenase 2; D000068579:Celecoxib