Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis.
Arthritis Res Ther
; 19(1): 47, 2017 03 07.
Article
en En
| MEDLINE
| ID: mdl-28270195
ABSTRACT
BACKGROUND:
The inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties.METHODS:
Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP.RESULTS:
We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation.CONCLUSIONS:
Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Artritis Experimental
/
Artritis Reumatoide
/
Naftoquinonas
/
Inmunosupresores
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Arthritis Res Ther
Asunto de la revista:
REUMATOLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Brasil