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. 2017 Jan 16:23:266-275.
doi: 10.12659/msm.901667.

Targeting of Wnt/β-Catenin by Anthelmintic Drug Pyrvinium Enhances Sensitivity of Ovarian Cancer Cells to Chemotherapy

Chongyuan Zhang  1 , Zhenge Zhang  1 , Shuirong Zhang  1 , Wenrong Wang  2 , Ping Hu  1
Affiliations

Targeting of Wnt/β-Catenin by Anthelmintic Drug Pyrvinium Enhances Sensitivity of Ovarian Cancer Cells to Chemotherapy

Chongyuan Zhang et al. Med Sci Monit. .

"VSports在线直播" Abstract

BACKGROUND Aberrant activation of Wnt/β-catenin has been shown to promote ovarian cancer proliferation and chemoresistance. Pyrvinium, an FDA-approved anthelmintic drug, has been identified as a potent Wnt inhibitor. Pyrvinium may sensitize ovarian cancer cells to chemotherapy. MATERIAL AND METHODS The effect of pyrvinium alone and its combination with paclitaxel in ovarian cancer was investigated using an in vitro culture system and in vivo xenograft models. The mechanisms of its action were also analyzed, focusing on the Wnt/β-catenin pathway. RESULTS Pyrvinium inhibited growth and induced apoptosis of paclitaxel- and cisplatin-resistant epithelial ovarian cancer cell lines A2278/PTX and SK-OV-3. Its combination with paclitaxel was synergistic in targeting ovarian cancer cells in vitro. In 3 independent ovarian xenograft mouse models, pyrvinium alone inhibited tumor growth VSports手机版. More importantly, we observed significant inhibition of tumor growth throughout the treatment when using pyrvinium and paclitaxel combined. Mechanistically, pyrvinium increased the Wnt-negative regulator axin and decreased the b-catenin levels in ovarian cancer cells. In addition, pyrvinium suppressed Wnt/b-catenin-mediated transcription, as shown by the decreased mRNA levels of MYC, cyclin D, and BCL-9. In contrast, the inhibitory effects of pyrvinium were reversed by β-catenin stabilization or overexpression, demonstrating that pyrvinium acted on ovarian cancer cells via targeting the Wnt/β-catenin signaling pathway. CONCLUSIONS We demonstrated that the anthelmintic drug pyrvinium targets ovarian cancer cells through suppressing Wnt/β-catenin signaling. Our work highlights the therapeutic value of inhibiting Wnt/β-catenin in ovarian cancer. .

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Conflict of interest statement (VSports)

All authors declare no conflict of interest.

Figures (VSports手机版)

Figure 1
Figure 1
Pyrvinium inhibits proliferation and induces apoptosis in ovarian cancer cell lines. (A) Representative flow cytometry dot plots showing the percentage of annexin V and PI staining. Pyrvinium significantly induces apoptosis (B) and inhibits proliferation (C) of SK-OV-3 and A2780/PTX cells in a dose-dependent manner. Cell were treated with pyrvinium for 3 days prior to proliferation and apoptosis analysis. These data are derived from 3 independent experiments. * p<0.05, compared to control.
Figure 2
Figure 2
Pyrvinium acts synergistically with paclitaxel in ovarian cancer cell lines. The combination of pyrvinium and paclitaxel inhibits much more proliferation (A) and induces much more apoptosis (B) than a single drug alone in SK-OV-3 and A2780/PTX cells. These data are derived from 3 independent experiments. The concentrations of pyrvinium and paclitaxel used in combination studies are 0.1 μM and 0.5 μM, respectively * p<0.05, compared to single-arm treatment.
Figure 3
Figure 3
Pyrvinium inhibits Wnt/β-catenin signaling in ovarian cancer cells. (A) Pyrvinium increases axin and decreases β-catenin levels in ovarian cancer cell lines. SK-OV-3 and A2780/PTX cells were treated with pyrvinium for 24 h. Cell lysates were immunoblotted for axin, β-catenin, and actin (loading control). (B) Pyrvinium inhibits TOPflash activation in ovarian cells. Cells transfected with TOPflash plasmid were treated as indicated. Results shown are relative to control. RLU, relative light units. Pyrvinium dose-dependently decreases mRNA levels of MYC, cyclin D, and BCL9 in SK-OV-3 (C) and A2780/PTX (D) cells. * p<0.05, compared to control.
Figure 4
Figure 4
The inhibitory effects of pyrvinium are abolished by β-catenin overexpression in ovarian cancer cells. (A) β-catenin levels are increased in ovarian cancer cells exposed to 1 mM LiCl or transfected with β-catenin overexpression plasmid in the presence or absence of pyrvinium. The inhibitory effects of pyrvinium on proliferation (B, C) or survival (D, E) were abolished by β-catenin overexpression. Cells were electroporated with 2 μg pcDNA or pcDNA-β-cat and cultured for 24 h prior to WB, MTS, apoptosis assays. * p<0.05, compared to wild-type cells.
Figure 5
Figure 5
The inhibitory effects of pyrvinium are abolished by LiCl in ovarian cancer cells. Pyrvinium is significantly less effective in inhibiting proliferation of SK-OV-3 (A) and A2778/PTX (B) cells. Pyrvinium is significantly less effective in inducing apoptosis of SK-OV-3 (C) and A27780/PTX (D) cells. One mM LiCl and pyrvinium at different concentrations were added in ovarian cancer cells for 3 days prior to proliferation and apoptosis analysis. Results shown are relative to control. * p<0.05, compared to wild-type cells.
Figure 6
Figure 6
Pyrvinium enhances the inhibitory effects of paclitaxel in vivo. Pyrvinium and paclitaxel inhibits ovarian tumor growth derived from SK-OV-3 (A) or A2780/PTX (B) cells. The combination of pyrvinium and paclitaxel synergistically arrests growth of ovarian cancer xenograft. Mice were treated with equal volume of vehicles, intraperitoneal pyrvinium at 0.5 mg/kg, and oral paclitaxel at 10 mg/kg or combination of both. (C) Representative Western blotting photos of cellular β-catenin in tumors are shown. * p<0.05, compared to single-arm treatment.
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