Antimalarial Drug Pyrimethamine Plays a Dual Role in Antitumor Proliferation and Metastasis through Targeting DHFR and TP.

Huijuan Liu,Tao Sun,Yuanhao Tang,Jiahuan Yang,Yuan Qin,Denghui Zhai,Shuang Chen,Qiang Zhang,Yanrong Liu,Ju Gu,Lan Yang,Kun Li,Jing Meng,Cheng Yang,Weilong Zhong

doi:10.1158/1535-7163.mct-18-0936

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 patients with lung cancer. In conclusion, Pyr plays a dual role in antitumor proliferation and metastasis by targeting DHFR and TP. Pyr may have potential clinical applications for the treatment of lung cancer.

Highlights

Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimidine, Pyr) has been clinically used as antimalarial drugs [1]
Our results showed that both MTX and Pyr could inhibit the activity of DHFR in lung cancer cells (Fig. 1A)
Pyrimethamine (Pyr) is a pyrimidine derivative, which interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by targeting DHFR of the plasmodium

Summary

Introduction

Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimidine, Pyr) has been clinically used as antimalarial drugs [1]. Pyr exerts its antimalarial effect by targeting plasmodium dihydrofolate reductase DHFR is an essential enzyme in the synthesis of folic acid, which is a cofactor required for DNA synthesis. In addition to its antimalarial effects, Pyr exhibits the activity of inducing apoptosis of tumor cells through cathepsin B–dependent and caspase–dependent apoptotic pathways [3, 4]. Pyr can inhibit the STAT3 pathway in breast cancer cells [5]. Pyr has a broad range of effects in non–small cell lung cancers [6]. The target of Pyr has not been elucidated before

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Conclusion