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1.
Pharmacol Res ; 205: 107244, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38821149

RESUMO

Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery vehicles are used to reduce Dox cardiotoxicity. Here, we substitute extracellular vesicles (EVs) for liposomes and deeply investigate the mechanism for EV-encapsulated Dox delivery. The results demonstrate that EVs dramatically increase import efficiency and anti-tumor effects of Dox in vitro and in vivo, and the efficiency increase benefits from its unique entry pattern. Dox-loading EVs repeat a "kiss-and-run" motion before EVs internalization. Once EVs touch the cell membrane, Dox disassociates from EVs and directly enters the cytoplasm, leading to higher and faster Dox import than single Dox. This unique entry pattern makes the adhesion between EVs and cell membrane rather than the total amount of EV internalization the key factor for regulating the Dox import. Furthermore, we recognize ICAM1 as the molecule mediating the adhesion between EVs and cell membranes. Interestingly, EV-encapsulated Dox can induce ICAM1 expression by irritating IFN-γ and TNF-α secretion in TME, thereby increasing tumor targeting of Dox-loading EVs. Altogether, EVs and EV-encapsulated Dox synergize via ICAM1, which collectively enhances the curative effects for tumor treatment.


Assuntos
Antibióticos Antineoplásicos , Doxorrubicina , Vesículas Extracelulares , Molécula 1 de Adesão Intercelular , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Animais , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efeitos dos fármacos , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Camundongos , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Adesão Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Camundongos Nus , Fator de Necrose Tumoral alfa/metabolismo
2.
Nat Commun ; 13(1): 3419, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35701426

RESUMO

TGF-ß is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-ß can greatly enhance antitumor immunity. However, there are still no effective TGF-ß inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-ß, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-ß at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-ß to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-ß at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-ß. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-ß regulation and implicate UDCA as a potential TGF-ß inhibitor to enhance antitumor immunity.


Assuntos
Neoplasias , Fator de Crescimento Transformador beta , Animais , Linhagem Celular Tumoral , Humanos , Terapia de Imunossupressão , Camundongos , Neoplasias/tratamento farmacológico , Estudos Retrospectivos , Fator de Crescimento Transformador beta/metabolismo , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
3.
Int Immunopharmacol ; 101(Pt A): 108191, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34601328

RESUMO

Neobavaisoflavone (Neo), is the active constituent of the herb Psoralea corylifolial, used in the traditional Chinese medicine, and has anti-inflammatory activity, but whether Neo could regulate colitis remains unclear. T helper 9 (TH9) cells, a subset of CD4+ T helper cells characterized by secretion of IL-9, have been reported to be involved in the pathogenesis of many autoimmune and inflammatory diseases, but whether Neo could control TH9 cell differentiation also remains unclear. Here, we found that Neo could decrease IL-9 production of CD4+ T cells by targeting PU.1 in vitro. Importantly, Neo had therapeutic effects on DSS-induced colitis. Furthermore, we identified TH9 cells as the direct target of Neo for attenuating bowel inflammation. Therefore, Neo could serve as a lead for developing new therapeutics against inflammatory bowel disease.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Colite/tratamento farmacológico , Isoflavonas/uso terapêutico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Colite/imunologia , Feminino , Imunofluorescência , Humanos , Immunoblotting , Isoflavonas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo Real
4.
Int Immunopharmacol ; 88: 106831, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32853925

RESUMO

The Chinese herbal medicine oridonin has potent anti-inflammatory and antitumor activities. In addition, oridonin treatment effectively suppresses breast cancer growth. However, the underlying mechanisms are poorly defined. Here, we reported that oridonin decreased Treg differentiation in vitro and in vivo. Oridonin inhibition of Treg differentiation was dependent on decreasing TGF-ß receptor expression. Oridonin attenuated Tregs' immunosuppressive ability; thus, oridonin did not inhibit CD8+ T cell proliferation very well in vitro. Oridonin greatly delayed the progression of 4T1 tumors in vivo. In addition, oridonin combined with anti-PD-1 activated a robust antitumor immune response and suppressed 4T1 tumor growth. Therefore, our results indicate that oridonin inhibits TNBC growth by modulating Treg differentiation, which provides new directions for the clinical treatment of TNBC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos do Tipo Caurano/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos
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