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

Zhou, Xumin; Zhang, Jinming; Hu, Xiaoping; He, Peiqing; Guo, Jianhua; Li, Jun; Lan, Tian; Liu, Jumei; Peng, Lilan; Li, Hua

doi:10.3389/fphar.2020.00758

Cited by 13 publications

(12 citation statements)

References 46 publications

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“…Pyrimethamine is known as an antifolate drug that blocks the parasitic dihydrofolate reductase (DHFR), which is essential for DNA and RNA synthesis. Recently it was reported that pyrimethamine can inhibit DHFR, thymidine phosphorylase (TP) [77], p38protein [78] and STAT3 transcriptional activity [79, 80] in human cells. The polypharmacological profiles of chloroquine and pyrimethamine motivated us to check their effect on the hRSV-A polymerase activity.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A

Rahman

Libre

Oleinikov

et al. 2021

Journal of General Virology

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Human respiratory syncytial virus (hRSV) is a major cause of respiratory illness in young children and can cause severe infections in the elderly or in immunocompromised adults. To date, there is no vaccine to prevent hRSV infections, and disease management is limited to preventive care by palivizumab in infants and supportive care for adults. Intervention with small-molecule antivirals specific for hRSV represents a good alternative, but no such compounds are currently approved. The investigation of existing drugs for new therapeutic purposes (drug repositioning) can be a faster approach to address this issue. In this study, we show that chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A (long strain) and synergistically increase the anti-replicative effect of ribavirin in cellulo. Moreover, chloroquine, but not pyrimethamine, inhibits hRSV replication in the mouse model. Our results show that chloroquine can potentially be an interesting compound for treatment of hRSV infection in monotherapy or in combination with other antivirals.

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Section: Discussionmentioning

confidence: 99%

Chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A

Rahman

Libre

Oleinikov

et al. 2021

Journal of General Virology

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“…These compounds have been shown to be safe in humans because they inhibit STAT3 at concentrations routinely achieved in human plasma ( Khan et al, 2018 ; Takakura et al, 2011 ; Xiang et al, 2016 ). To our knowledge, PYR and AQ have yet to be specifically assessed in endothelium, as prior studies have primarily evaluated their STAT3 inhibitory effects on tumor cells of epithelial origin ( Cheng et al, 2020 ; Coates et al, 2020 ; Khan et al, 2018 ; Lin et al, 2018 ; Liu et al, 2019a , b ; Wu et al, 2020 ; Xiang et al, 2016 ; Zhou et al, 2020 ). Therefore, we first treated HUVECs with various concentrations of PYR or AQ for different durations to determine the optimal conditions, while not exceeding the concentrations typically achieved in human plasma ( …”

Section: Resultsmentioning

confidence: 99%

Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

Wang

Astone

Alam

et al. 2021

Disease Models &Amp; Mechanisms

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Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, including cancer, stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema, sepsis, and acute lung injury. Understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics to inhibit vascular permeability, while preserving tissue-restorative angiogenesis. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. We show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated Stat3 knockout zebrafish. Intercellular adhesion molecule 1 (ICAM-1) expression is transcriptionally regulated by STAT3 and VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved anti-microbial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse, and human endothelium. Collectively, our findings suggest that VEGF/VEGFR-2/JAK2/STAT3 signaling regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability.

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“…Zhou et al evaluated the potency of pyrimethamine against CRPC (DU145 and PC3) cells. Pyrimethamine significantly reduced the viability, induced the cell cycle arrest in the S‐phase, and promoted the apoptosis of CRPC cells 84 . The proapoptotic effect of pyrimethamine was evidenced by the decrease in the expression of antiapoptotic proteins (such as Bcl‐2 and Bcl‐xL).…”

Section: Antineoplastic Effects Of Pyrimethaminementioning

confidence: 99%

The multifaceted antineoplastic role of pyrimethamine against human malignancies

et al. 2022

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Cancer accounted for nearly 10 million deaths in 2020 and is the second leading cause of death worldwide. The chemotherapeutic agents that are in clinical practice possess a broad range of severe adverse effects towards vital organs which emphasizes the importance of the discovery of new therapeutic agents or repurposing of existing drugs for the treatment of human cancers. Pyrimethamine is an antiparasitic drug used for the treatment of malaria and toxoplasmosis with a well‐documented excellent safety profile. In the last 5 years, numerous efforts have been made to explore the anticancer potential of pyrimethamine in in vitro and in vivo preclinical models and to repurpose it as an anticancer agent. The studies have demonstrated that pyrimethamine inhibits oncogenic proteins such as STAT3, NF‐κB, DX2, MAPK, DHFR, thymidine phosphorylase, telomerase, and many more in a different types of cancer models. Moreover, pyrimethamine has been reported to work in synergy with other anticancer agents, such as temozolomide, to induce apoptosis of tumor cells. Recently, the results of phase‐1/2 clinical trials demonstrated that pyrimethamine administration reduces the expression of STAT3 signature genes in tumor tissues of chronic lymphocytic leukemia patients with a good therapeutic response. In the present article, we have reviewed most of the published articles related to the antitumor effects of pyrimethamine in malignancies of breast, liver, lung, skin, ovary, prostate, pituitary, and leukemia in in vitro and in vivo settings. We have also discussed the pharmacokinetic profile and results of clinical trials obtained after pyrimethamine treatment. From these studies, we believe that pyrimethamine has the potential to be repurposed as an anticancer drug.

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

Cited by 13 publications

References 46 publications

Chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A

Chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A

Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

The multifaceted antineoplastic role of pyrimethamine against human malignancies

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