<i>In Vitro</i>and<i>In Vivo</i>Antitumor Effects of Pyrimethamine on Non-small Cell Lung Cancers

Lin, Meng-Xian; Lin, Sheng‐Hao; Lin, Chi-Chen; Yang, Ching‐Chieh; Yuan, Sheau-Yun

doi:10.21873/anticanres.12612

Cited by 17 publications

(15 citation statements)

References 15 publications

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“…After treatment with pyrimethamine, we observed that pyrimethamine significantly inhibited the growth of DX2-inducible A549 cells compared to EV-inducible A549 cells ( Figure 3 ). Pyrimethamine was reported to show the anti-tumor effect against cancer cells [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], but its mechanism was still veiled [ 19 ]. Our results showed that the increased level of DX2 leads the strong anti-tumor effect, suggesting that DX2 could be one of the targets for pyrimethamine-mediated anti-tumoral effect.…”

Section: Resultsmentioning

confidence: 99%

“…Pyrimethamine was launched in 1953 for the treatment of malaria as a dihydrofolate reductase (DHFR) inhibitor ( ), and more recently for the treatment of toxoplasmosis combined with a sulfonamide [ 13 , 14 ]. Pyrimethamine also has been widely studied for the treatment of advanced solid tumors such as lung cancer, ovarian cancer, triple negative breast cancer, and chronic lymphocytic leukemia based on the various mechanisms including signal transducer and activator of transcription 3 (STAT3) inhibition [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], differently from DX2 inhibition.…”

Section: Introductionmentioning

confidence: 99%

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Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2

et al. 2020

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While aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is highly expressed in human lung cancer, and the ratio of DX2 to AIMP2 increases according to the progression of lung cancer. In this study, pyrimethamine inhibited the level of DX2 (IC50 = 0.73 µM) in A549 cells expressing nanoluciferase-tagged DX2. In a panel of 5 lung cancer cell lines with various DX2 levels, pyrimethamine most potently suppressed the growth of H460 cells, which express high levels of DX2 (GI50 = 0.01 µM). An immunoblot assay in H460 cells showed that pyrimethamine decreased the DX2 level dose-dependently but did not affect the AIMP2 level. Further experiments confirmed that pyrimethamine resulted in ubiquitination-mediated DX2 degradation. In an in vivo mouse xenograft assay using H460 cells, intraperitoneal administration of pyrimethamine significantly reduced the tumor size and weight, comparable with the effects of taxol, without affecting body weight. Analysis of tumor tissue showed a considerably high concentration of pyrimethamine with a decreased levels of DX2. These results suggest that pyrimethamine, currently used as anti-parasite drug, could be repurposed to treat lung cancer patients expressing high level of DX2.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2

et al. 2020

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“…It is used to treat infections caused by protozoan parasites, such as Plasmodium falciparum and Toxoplasma gondii (Masur et al, 2000;Mockenhaupt et al, 2001;Hill and Dubey, 2002). In addition to its antimalarial effects, several studies have reported that pyrimethamine might be beneficial in the treatment of different types of tumors, including lung cancer (Lin et al, 2018), melanoma (Giammarioli et al, 2008;Tommasino et al, 2016), breast cancer (Khan et al, 2018), and acute myeloid leukemia (Sharma et al, 2016). It has been suggested that the mechanism underlying this activity involves the induction of cathepsin B-dependent and caspase-dependent apoptotic pathways, inhibition of STAT3, activation of the Caspase8/9, and cell cycle arrest in S-phase.…”

Section: Introductionmentioning

confidence: 99%

Pyrimethamine Elicits Antitumor Effects on Prostate Cancer by Inhibiting the p38-NF-κB Pathway

Zhou

Zhang

et al. 2020

Front. Pharmacol.

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Since incurable castration-resistant prostate cancer (CRPC) inevitably develops following treatment with androgen deprivation therapy, there is an urgent need to devise new therapeutic strategies to treat this cancer. Pyrimethamine, an FDA-approved antimalarial drug, is known to exert an antitumor activity in various types of human cancer cells. However, whether pyrimethamine can inhibit prostate cancer is not well established. Hence, the present study aimed to characterize the mechanism of action of pyrimethamine on prostate cancer. We investigated the potential effect of pyrimethamine on cell proliferation, cell cycle, and apoptosis in metastatic DU145 and PC3 prostate cancer cells. We found that pyrimethamine inhibited cell proliferation, induced cell cycle arrest in the S phase, and promoted cell apoptosis of prostate cells in vitro; it also suppressed tumor growth in xenograft models. In addition, we observed that pyrimethamine suppressed prostate cancer growth by inhibiting the p38-NF-kB axis in vitro and in vivo. Thus, this study demonstrates that pyrimethamine is a novel p38 inhibitor that can exert antiproliferative and proapoptotic effects in prostate cancer by affecting cell cycle and intrinsic apoptotic signaling, thereby providing a novel strategy for using pyrimethamine in CRPC treatment.

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“…Pyr can also inhibit the STAT3 pathway in breast cancer cells (5). Pyr also has a broad range of effects in non-small cell lung cancers (6). However, the target of Pyr has not been elucidated before.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Qin

Zhai

et al. 2019

Molecular Cancer Therapeutics

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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.

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In VitroandIn VivoAntitumor Effects of Pyrimethamine on Non-small Cell Lung Cancers

Abstract: PYR demonstrated anti-tumour effects on NSCLC in vitro and in vivo, indicating its therapeutic potential against human NSCLC.

Cited by 17 publications

References 15 publications

Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2

Anticancer Activity of Pyrimethamine via Ubiquitin Mediated Degradation of AIMP2-DX2

Pyrimethamine Elicits Antitumor Effects on Prostate Cancer by Inhibiting the p38-NF-κB Pathway

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

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