Betulin Attenuates TGF-ß1- and PGE2-Mediated Inhibition of NK Cell Activity to Suppress Tumor Progression and Metastasis in Mice.
Biol Pharm Bull
; 45(3): 339-353, 2022.
Article
em En
| MEDLINE
| ID: mdl-35228400
ABSTRACT
Transforming growth factor (TGF)-ß1 and prostaglandin E2 (PGE2) are humoral factors critically involved in the induction of immunosuppression in the microenvironment of various types of tumors, including melanoma. In this study, we identified a natural compound that attenuated TGF-ß1- and PGE2-induced immunosuppression and examined its effect on B16 melanoma growth in mice. By screening 502 natural compounds for attenuating activity against TGF-ß1- or PGE2-induced suppression of cytolysis in poly(IC)-stimulated murine splenocytes, we found that betulin was the most potent compound. Betulin also reduced TGF-ß1- and PGE2-induced downregulation of perforin and granzyme B mRNA expression and cell surface expression of NKG2D and CD69 in natural killer (NK) cells. Cell depletion and coculture experiments showed that NK cells, dendritic cells, B cells, and T cells were necessary for the attenuating effects of betulin. Structure-activity relationship analysis revealed that two hydroxyl groups at positions C3 and C28 of betulin, their cis-configuration, and methyl group at C30 played crucial roles in its attenuating activity. In a subcutaneous implantation model of B16 melanoma in mice, intratumor administration of betulin and LY2157299, a TGF-ß1 type I receptor kinase inhibitor, significantly retarded the growth of B16 melanoma. Notably, betulin increased significantly the number of CD69 positive NK cells in tumor sites at early stages of post-tumor cell injection. Our data suggest that betulin inhibits the growth of B16 melanoma by enhancing NK cell activity through attenuating the immunosuppressive tumor microenvironment.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triterpenos
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Melanoma Experimental
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Dinoprostona
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Fator de Crescimento Transformador beta1
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Biol Pharm Bull
Assunto da revista:
BIOQUIMICA
/
FARMACOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article