title: Mitogen-activated Protein Kinase Kinase 6-fusion Protein (MAP2K6-FP) Potentiates the Anti-tumor effects of Paclitaxel in Ovarian Cancer.
abstract: OBJECTIVE
  To investigate the antitumor effects of a mitogen-activated protein kinase (MAPK) kinase fusion protein, TAT-OSBP-MKK6E (MAP2K6-FP), and paclitaxel as single agents and in combination against HO8910 human ovarian cancer cells.
  
  
  METHODS
  We previously synthesized a MAPK kinase-recombinant fusion protein, MAP2K6-FP, that contains three domains: a protein transduction domain TAT, a human ovarian cancer HO8910 cell-specific binding peptide (OSBP), and a potential anti-tumor effector domain MKK6 (E). The HO8910 cells were exposed to MAP2K6-FP, paclitaxel, or both for 24 h. The antiproliferative effects were determined using the Cell Counting Kit-8 assay. Antitumor synergy was determined by computing the combination index. The in vivo antitumor effects of both drugs as single agents and in combination were tested using HO8910 cells implanted subcutaneously in female BALBC/c nude mice. TUNEL assay, immunohistochemical evaluation, and western blotting were performed to investigate the mechanism of action.
  
  
  RESULTS
  A synergistic anti-proliferative effect was observed between MAP2K6-FP and paclitaxel at multiple drug concentrations, resulting in combination indices ranging from 0.3-0.85. In vivo testing against HO8910 cells in a xenograft tumor model indicated that both drugs were effective as single agents and that MAP2K6-FP and paclitaxel in combination had a synergistic antitumor effect. The combination treatment resulted in significantly altered caspase-3, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigen expression compared to treatment with the single agents (P<0.05).
  
  
  CONCLUSIONS
  Both MAP2K6-FP and paclitaxel can inhibit cell proliferation and induce apoptosis in ovarian cancer HO8910 cells. Interestingly, the combination of MAP2K6-FP and paclitaxel had a synergistic antitumor effect on HO8910 cells, which induced apoptosis by increasing caspase-3 expression and decreasing VEGF expression.
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Obstetrics and Gynecology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, PR China. kangjiali1961@21cn.com.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Kang
authors.forename: Hua
authors.initials: H
authors.lastname: Liao
authors.forename: Xiao-xia
authors.initials: XX
authors.lastname: Wang
authors.forename: Miao-lin
authors.initials: ML
authors.lastname: Nie
authors.forename: Rong
authors.initials: R
authors.lastname: Shuai
authors.forename: Cui
authors.initials: C
authors.lastname: Deng
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D064593:Heterografts; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011993:Recombinant Fusion Proteins; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D017239:Paclitaxel