Mitogen-activated Protein Kinase Kinase 6-fusion Protein (MAP2K6-FP) Potentiates the Anti-tumor effects of Paclitaxel in Ovarian Cancer

Author(s): Jin Yuan , Jia-Li Kang , Hua Liao , Xiao-xia Wang , Miao-lin Nie , Rong Shuai , Cui Deng .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 15 , Issue 10 , 2015

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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-8assay. Antitumor synergy was determined by computing the combinationindex. 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 treatmentresulted in significantly alteredcaspase-3, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigenexpression compared to treatment with the single agents (P<0.05).

Conclusion: 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.

Keywords: MAPK kinase, mitogen-activated protein kinase, TAT-OSBP-MKK6(E), fusion protein, paclitaxel, ovarian cancer, apoptosis, combination therapy.

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Article Details

VOLUME: 15
ISSUE: 10
Year: 2015
Page: [1308 - 1316]
Pages: 9
DOI: 10.2174/1871520615666150629100405
Price: $58

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