title: Synergistic anti-tumor activity and mechanisms of total glycosides from Cimicifuga dahurica in combination with cisplatin.
abstract: OBJECTIVE
  To determine the effect and mechanism of combination treatment of the total glycosides from Cimicifuga dahurica (TGCD) and cisplatin (CDDP) in vitro in human colon cancer cells (HCT-8) and in vivo in mouse hepatoma cells (H22)-bearing mice.
  
  
  METHODS
  H22 tumor-bearing imprinting control region (ICR) mice were treated with TGCD, CDDP, and TGCD + CDDP for 10 days. Tumor volume and tumor weight were evaluated. TGCD and CDDP in different concentrations were added separately and in combination to cultures of different cancer cell lines, including the HCT-8. Effects of TGCD and CDDP on cell proliferation were detected by 3-(4,5-dimethyl-2-thiazole)-2-5-biphenly-tetrazole bromide (MTT) method and effects on cell apoptosis were tested by flfl ow cytometry and western blotting at 24 h after treatment.
  
  
  RESULTS
  Combination index values (CI<0.8) suggested the synergistic effects of the TGCD + CDDP. This combination resulted in the highest increase in the percentage of apoptotic HCT-8 cells, caused cell cycle arrest in G2/M phase and increased expression of cleaved caspase-3, -8, and -9, Bax, phospho-c-Jun N-terminal kinase (p-JNK), and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK), as well as decreased expression of Bcl-2, JNK, p38 MAPK, Poly (ADP-ribose) polymerase 1 (PARP1), caspase-3, and caspase-8 compared with single-agent treated and control groups. TGCD + CDDP treatment reduced tumor weight by 86.1%±7.2% compared with 64.5%±6.8% by CDDP or 46.9%±6.9% by the TGCD alone in vivo.
  
  
  CONCLUSIONS
  TGCD enhanced the anticancer activity of CDDP in an additive-to-synergistic manner by activating multiple signaling pathways (including apoptosis). These fifi ndings suggest the potential benefifi t of combined treatment of the TGCD and CDDP against cancer of the colon and liver.
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Si
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
authors.forename: Li-Jing
authors.initials: LJ
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
authors.forename: Huo
authors.initials: H
authors.lastname: Xiao-Wei
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Biomedical Engineering and Instrumental Science of Zhejiang University, Hangzhou, 310027, China.
authors.forename: Ru-Yi
authors.initials: RY
authors.lastname: Li
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.|Research Division of Pharmacology, Guiyang Medical College, Guiyang, 550004, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China. lcao@implad.ac.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
keywords: cisplatin; colon cancer; synergism apoptosis; total glycosides from Cimicifuga dahurica