State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
College of Life Sciences, Nankai University, Tianjin, China.
Mol Cancer Ther. 2019 Mar;18(3):541-555. doi: 10.1158/1535-7163.MCT-18-0936. Epub 2019 Jan 14.
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 and 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.
伯氨喹（Pyr）是一种抗疟药物，靶向疟原虫二氢叶酸还原酶（pDHFR），已被证明具有抗肿瘤活性。然而，其对癌细胞的直接靶点尚不清楚。甲氨蝶呤（MTX）是一种广泛用于阻断人二氢叶酸还原酶（hDHFR）的抗癌药物。在这项工作中，我们研究了 Pyr 和 MTX 对肺癌细胞的抗肿瘤作用。结果表明，hDHFR 和 pDHFR 具有相似的二级和三维结构，Pyr 可以抑制肺癌细胞中 hDHFR 的活性。尽管 Pyr 和 MTX 可以通过靶向 DHFR 抑制肺癌细胞的增殖，但只有 Pyr 可以抑制肺癌细胞的上皮-间充质转化（EMT）、转移和侵袭。这些结果表明 hDHFR 不是 Pyr 的唯一靶点。我们进一步发现，与癌细胞 EMT 密切相关的酶胸苷磷酸化酶（TP）也是 Pyr 的靶蛋白。从癌症基因组图谱（TCGA）数据库中检索到的数据表明，TP 过表达与肺癌患者的预后不良相关。总之，Pyr 通过靶向 DHFR 和 TP 在抗肿瘤增殖和转移中发挥双重作用。Pyr 可能具有治疗肺癌的潜在临床应用价值。
