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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Antimalarial drug pyrimethamine plays a dual role in anti-tumor proliferation and metastasis through targeting DHFR and TP

Huijuan Liu, Yuan Qin, Denghui Zhai, Qiang Zhang, Ju Gu, Yuanhao Tang, Jiahuan Yang, Kun Li, Lan Yang, Shuang Chen, Weilong Zhong, Jing Meng, Yanrong Liu, Tao Sun and Cheng Yang
Huijuan Liu
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University
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  • For correspondence: liuhuijuanxyz@163.com
Yuan Qin
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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Denghui Zhai
college of pharmacy, Nankai University
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Qiang Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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Ju Gu
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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Yuanhao Tang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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Jiahuan Yang
State Key Laboratory of Medicinal Chemical Biology, Nankai University
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Kun Li
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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Lan Yang
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine
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Shuang Chen
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine
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  • ORCID record for Shuang Chen
Weilong Zhong
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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Jing Meng
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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Yanrong Liu
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine
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Tao Sun
State Key Laboratory of Medicinal Chemical Biology, Nankai University
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Cheng Yang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University
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DOI: 10.1158/1535-7163.MCT-18-0936
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Abstract

Pyrimethamine (Pyr), an antimalarial drug that targeting plasmodium dihydrofolate reductase (pDHFR), has been proved to have antitumor activity. However, its direct target on cancer cells remains unclear. Methotrexate (MTX) is a widely used anticancer drug that blocks human dihydrofolate reductase (hDHFR). In this work, we examined the anticancer effects of Pyr in vitro and in vivo. Our results showed that hDHFR and pDHFR have similar secondary and three-dimensional structures and that Pyr can inhibit the activity of hDHFR in lung cancer cells. Although Pyr and MTX can inhibit the proliferation of lung cancer cells by targeting DHFR, only Pyr can inhibit the epithelial-mesenchymal transition (EMT), metastasis and invasion of lung cancer cells. These results indicated that hDHFR is not the only target of Pyr. We further found that thymidine phosphorylase (TP), an enzyme that is closely associated with the EMT of cancer cells, is also a target protein of Pyr. The data retrieved from the Cancer Genome Atlas (TCGA) database revealed that TP overexpression is associated with poor prognosis of lung cancer patients. In conclusion, Pyr plays a dual role in anti-tumor proliferation and metastasis by targeting DHFR and TP. Pyr may have potential clinical applications for the treatment of lung cancer.

  • Received August 16, 2018.
  • Revision received November 16, 2018.
  • Accepted January 11, 2019.
  • Copyright ©2019, American Association for Cancer Research.
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Published OnlineFirst January 14, 2019
doi: 10.1158/1535-7163.MCT-18-0936

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Antimalarial drug pyrimethamine plays a dual role in anti-tumor proliferation and metastasis through targeting DHFR and TP
Huijuan Liu, Yuan Qin, Denghui Zhai, Qiang Zhang, Ju Gu, Yuanhao Tang, Jiahuan Yang, Kun Li, Lan Yang, Shuang Chen, Weilong Zhong, Jing Meng, Yanrong Liu, Tao Sun and Cheng Yang
Mol Cancer Ther January 14 2019 DOI: 10.1158/1535-7163.MCT-18-0936

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Antimalarial drug pyrimethamine plays a dual role in anti-tumor proliferation and metastasis through targeting DHFR and TP
Huijuan Liu, Yuan Qin, Denghui Zhai, Qiang Zhang, Ju Gu, Yuanhao Tang, Jiahuan Yang, Kun Li, Lan Yang, Shuang Chen, Weilong Zhong, Jing Meng, Yanrong Liu, Tao Sun and Cheng Yang
Mol Cancer Ther January 14 2019 DOI: 10.1158/1535-7163.MCT-18-0936
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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