ArticleThe Journal of biological chemistry2016
Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 41 citations in OpenAlex.
- Identification of potential mechanisms of ferulic acid in inflammatory bowel disease through integrated network pharmacology and experimental validation.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- PACSIN2 regulates mercaptopurine cytotoxicity and cellular biomechanics through Rac1 modulation in intestinal epithelial cells.Frontiers in pharmacology · 2026Article
- Contemporary and prospective use of azathioprine (AZA) in viral, rheumatic, and dermatological disorders: a review of pharmacogenomic and nanotechnology applications.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- 6-thioguanine inhibits EV71 replication by reducing BIRC3-mediated autophagy.BMC microbiology · 2025Article
- Cheese starter cultures attenuate inflammation in the in vitro Caco-2 model.AIMS microbiology · 2025Article
- Vav proteins do not influence dengue virus replication but are associated with induction of phospho-ERK, IL-6, and viperin mRNA following DENV infectionMicrobiology spectrum · 2024Article
- Effects of genetic and clinical factors on thiopurine drugs pharmacokinetics in Tunisian patients.Pharmacogenomics · 2024Article
- Clinical Management of Herpes Simplex Virus Keratitis.Diagnostics (Basel, Switzerland) · 2022Review
- Thiopurines inhibit coronavirus Spike protein processing and incorporation into progeny virions.PLoS pathogens · 2022Article
- 6-Thioguanine Inhibits Herpes Simplex Virus 1 Infection of Eyes.Microbiology spectrum · 2021Article
- Thiopurines activate an antiviral unfolded protein response that blocks influenza A virus glycoprotein accumulation.Journal of virology · 2021Article
- Treatment of Inflammatory Bowel Disease: A Comprehensive Review.Frontiers in medicine · 2021Review
- Development of Noonan syndrome by deregulation of allosteric SOS autoactivation.The Journal of biological chemistry · 2020Article
- Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts.Journal of clinical medicine · 2020Review
- Optimizing the Use of Current Treatments and Emerging Therapeutic Approaches to Achieve Therapeutic Success in Patients with Inflammatory Bowel Disease.Gut and liver · 2020Review
- Mosaic Tetrasomy 9p Associated With Inflammatory Bowel Disease.Journal of Crohn's & colitis · 2019Article
- Pharmacogenetics of thiopurines.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- 6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling.Antiviral research · 2018Article
- Advances in autoimmune myasthenia gravis management.Expert review of neurotherapeutics · 2018Review
- Pharmacological targeting of allergen-specific T lymphocytes.Immunology letters · 2017Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
6-Thiopurine (6-TP) prodrugs include 6-thioguanine and azathioprine. Both are widely used to treat autoimmune disorders and certain cancers. This study showed that a 6-thioguanosine triphosphate (6-TGTP), converted in T-cells from 6-TP, targets Rac1 to form a disulfide adduct between 6-TGTP and the redox-sensitive GXXXXGK(S/T)C motif of Rac1. This study also showed that, despite the conservation of the catalytic activity of RhoGAP (Rho-specific GAP) on the 6-TGTP-Rac1 adduct to produce the biologically inactive 6-thioguanosine diphosphate (6-TGDP)-Rac1 adduct, RhoGEF (Rho-specific GEF) cannot exchange the 6-TGDP adducted on Rac1 with free guanine nucleotide. The biologically inactive 6-TGDP-Rac1 adduct accumulates in cells because of the ongoing combined actions of RhoGEF and RhoGAP. Because other Rho GTPases, such as RhoA and Cdc42, also possess the GXXXXGK(S/T)C motif, the proposed mechanism for the inactivation of Rac1 also applies to RhoA and Cdc42. However, previous studies have shown that CD3/CD28-stimulated T-cells contain more activated Rac1 than other Rho GTPases such as RhoA and Cdc42. Accordingly, Rac1 is the main target of 6-TP in activated T-cells. This explains the T-cell-specific Rac1-targeting therapeutic action of 6-TP that suppresses the immune response. This proposed mechanism for the action of 6-TP on Rac1 performs a critical role in demonstrating the capability to design a Rac1-targeting chemotherapeutic agent(s) for autoimmune disorders. Nevertheless, the results also suggest that the targeting action of other Rho GTPases in other organ cells, such as RhoA in vascular cells, may be linked to cytotoxicities because RhoA plays a key role in vasculature functions.
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