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1.
PLoS One ; 19(6): e0304985, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38843278

RESUMO

Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.


Assuntos
Antígenos de Diferenciação , Antígeno CD47 , Imunoconjugados , Receptores Imunológicos , Antígeno CD47/antagonistas & inibidores , Antígeno CD47/imunologia , Animais , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores Imunológicos/imunologia , Humanos , Camundongos , Imunoconjugados/farmacologia , Antígenos de Diferenciação/imunologia , Linhagem Celular Tumoral , Feminino , Trastuzumab/farmacologia , Inibidores da Topoisomerase I/farmacologia , Imunoterapia/métodos , Camundongos Endogâmicos BALB C
2.
ACS Appl Mater Interfaces ; 13(27): 31928-31933, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34192877

RESUMO

Molecule-based ferroelectrics has attracted much attention because of its advantages, such as flexibility, light weight, and low environmental load. In the present work, we examined an organic metal|insulator|semiconductor|insulator|metal (MISIM) device structure to stabilize the interfacial polarization in the S layer and to induce polarization hysteresis even without bulk ferroelectrics. The MISIM devices with I = parylene C and S = TMB (=3,3',5,5'-tetramethylbenzidine)-TCNQ (=tetracyanoquinodimethane) exhibited hysteresis loops in the polarization-voltage (P-V) curves not only at room temperature but also over a wide temperature range down to 80 K. The presence of polarization hysteresis for MISIM devices was theoretically confirmed by an electrostatic model, which also explained the observed thickness dependence of the I layers on the P-V curves. Polarization hysteresis curves were also obtained in MISIM devices using typical organic semiconductors (ZnPc, C60, and TCNQ) as the S layer, demonstrating the versatility of the interfacial polarization mechanism.

3.
J Pharm Pharmacol ; 69(1): 43-51, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27757958

RESUMO

OBJECTIVES: Recently, there has been a growing interest in the mechanism of action of dichloroacetate (DCA) for T-cell differentiation; however, this mechanism has not been elucidated in detail. Therefore, this study aimed to investigate the mechanism of action of DCA for Treg and Th17 differentiation with pyruvate dehydrogenase kinase (PDHK) inhibitor (AZD7545) and PDHK knockdown. METHODS: Inhibitory activity of DCA and AZD7545 against recombinant PDHK and intracellular PDH phosphorylation was measured. The effects of DCA and AZD7545 on T-cell differentiation were assessed by analysing Foxp3+ T-cell populations for Treg differentiation and IL-17A production for Th17 differentiation. For reactive oxygen species (ROS) production, DCFDA was used as an indicator. KEY FINDINGS: Dichloroacetate and AZD7545 inhibited PDHK activity of recombinant PDHK and intracellular PDH phosphorylation. DCA was capable of inducing Treg differentiation and suppressing Th17 differentiation. The effects of DCA were independent of PDHK because neither AZD7545 nor knockdown of PDHK1 or PDHK3 affected T-cell differentiation. DCA was determined to be capable of inducing ROS production, and the effects of DCA on T-cell differentiation were shown to be dependent on ROS production. CONCLUSIONS: Dichloroacetate possesses Treg induction and Th17 suppression, which is independent of PDHK and dependent on ROS production.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Ácido Dicloroacético/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia , Anilidas/farmacologia , Animais , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Piruvato Desidrogenase Quinase de Transferência de Acetil
4.
J Med Chem ; 58(10): 4204-19, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25970039

RESUMO

Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.


Assuntos
Lisofosfolipídeos/química , Receptores Acoplados a Proteínas G/agonistas , Receptores de Lisofosfolipídeos/agonistas , Receptores Purinérgicos P2/efeitos dos fármacos , Relação Estrutura-Atividade , Aminoácidos/química , Técnicas de Química Sintética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Glicerol/química , Células HEK293 , Humanos , Estrutura Molecular , Fibras de Estresse/efeitos dos fármacos , Fibras de Estresse/metabolismo , Fator de Crescimento Transformador alfa/metabolismo
5.
J Biochem ; 157(3): 151-60, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25320102

RESUMO

Lysophosphatidylserine (1-oleoyl-2 R-lysophosphatidylserine, LysoPS) has been shown to have lipid mediator-like actions such as stimulation of mast cell degranulation and suppression of T lymphocyte proliferation, although the mechanisms of LysoPS actions have been elusive. Recently, three G protein-coupled receptors (LPS1/GPR34, LPS2/P2Y10 and LPS3/GPR174) were found to react specifically with LysoPS, raising the possibility that LysoPS serves as a lipid mediator that exerts its role through these receptors. Previously, we chemically synthesized a number of LysoPS analogues and evaluated them as agonists for mast-cell degranulation. Here, we used a transforming growth factor-α (TGFα) shedding assay to see if these LysoPS analogues activated the three LysoPS receptors. Modification of the serine moiety significantly reduced the ability of the analogues to activate the three LysoPS receptors, whereas modification of other parts resulted in loss of activity in receptor-specific manner. We found that introduction of methyl group to serine moiety (1-oleoyl-lysophosphatidylallothreonine) and removal of sn-2 hydroxyl group (1-oleoyl-2-deoxy-LysoPS) resulted in reduction of reactivity with LPS1 and LPS3, respectively. Accordingly, we synthesized a LysoPS analogue with the two modifications (1-oleoyl-2-deoxy-lysophosphatidylallothreonine) and found it to be an LPS2-selective agonist. These pharmacological tools will definitely help to identify the biological roles of these LysoPS receptors.


Assuntos
Lisofosfolipídeos/farmacologia , Fosfatidilserinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Lisofosfolipídeos/metabolismo , Receptores Purinérgicos P2/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Concentração Inibidora 50 , Receptores Acoplados a Proteínas G/agonistas , Receptores de Lisofosfolipídeos/agonistas , Transdução de Sinais , Fator de Crescimento Transformador alfa/metabolismo
6.
J Lipid Res ; 55(10): 1986-95, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24891334

RESUMO

It is now accepted that lysophospholipids (LysoGPs) have a wide variety of functions as lipid mediators that are exerted through G protein-coupled receptors (GPCRs) specific to each lysophospholipid. While the roles of some LysoGPs, such as lysophosphatidic acid and sphingosine 1-phosphate, have been thoroughly examined, little is known about the roles of several other LysoGPs, such as lysophosphatidylserine (LysoPS), lysophosphatidylthreonine, lysophosphatidylethanolamine, lysophosphatidylinositol (LPI), and lysophosphatidylglycerol. Recently, a GPCR was found for LPI (GPR55) and three GPCRs (GPR34/LPS1, P2Y10/LPS2, and GPR174/LPS3) were found for LysoPS. In this review, we focus on these newly identified GPCRs and summarize the actions of LysoPS and LPI as lipid mediators.


Assuntos
Lisofosfolipídeos , Receptores de Lisofosfolipídeos , Animais , Humanos , Lisofosfolipídeos/química , Lisofosfolipídeos/metabolismo , Receptores de Lisofosfolipídeos/química , Receptores de Lisofosfolipídeos/genética , Receptores de Lisofosfolipídeos/metabolismo , Relação Estrutura-Atividade
7.
Nat Methods ; 9(10): 1021-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22983457

RESUMO

A single-format method to detect multiple G protein-coupled receptor (GPCR) signaling, especially Gα(12/13) signaling, presently has limited throughput and sensitivity. Here we report a transforming growth factor-α (TGFα) shedding assay, in which GPCR activation is measured as ectodomain shedding of a membrane-bound proform of alkaline phosphatase-tagged TGFα (AP-TGFα) and its release into conditioned medium. AP-TGFα shedding response occurred almost exclusively downstream of Gα(12/13) and Gα(q) signaling. Relying on chimeric Gα proteins and promiscuous Gα(16) protein, which can couple with Gα(s)- and Gα(i)-coupled GPCRs and induce Gα(q) signaling, we used the TGFα shedding assay to detect 104 GPCRs among 116 human GPCRs. We identified three orphan GPCRs (P2Y10, A630033H20 and GPR174) as Gα(12/13)-coupled lysophosphatidylserine receptors. Thus, the TGFα shedding assay is useful for studies of poorly characterized Gα(12/13)-coupled GPCRs and is a versatile platform for detecting GPCR activation including searching for ligands of orphan GPCRs.


Assuntos
Receptores Acoplados a Proteínas G/análise , Fator de Crescimento Transformador alfa/fisiologia , Animais , Células CHO , Cricetinae , Cricetulus , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Células HEK293 , Humanos , Lisofosfolipídeos/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Receptores Purinérgicos P2/metabolismo , Transdução de Sinais
8.
EMBO J ; 30(20): 4248-60, 2011 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-21857648

RESUMO

Recent genetic studies of human hair disorders have suggested a critical role of lysophosphatidic acid (LPA) signalling in hair follicle development, mediated by an LPA-producing enzyme, phosphatidic acid-selective phospholipase A(1)α (PA-PLA(1)α, also known as LIPH), and a recently identified LPA receptor, P2Y5 (also known as LPA(6)). However, the underlying molecular mechanism is unknown. Here, we show that epidermal growth factor receptor (EGFR) signalling underlies LPA-induced hair follicle development. PA-PLA(1)α-deficient mice generated in this study exhibited wavy hairs due to the aberrant formation of the inner root sheath (IRS) in hair follicles, which resembled mutant mice defective in tumour necrosis factor α converting enzyme (TACE), transforming growth factor α (TGFα) and EGFR. PA-PLA(1)α was co-localized with TACE, TGFα and tyrosine-phosphorylated EGFR in the IRS. In PA-PLA(1)α-deficient hair follicles, cleaved TGFα and tyrosine-phosphorylated EGFR, as well as LPA, were significantly reduced. LPA, P2Y5 agonists and recombinant PA-PLA(1)α enzyme induced P2Y5- and TACE-mediated ectodomain shedding of TGFα through G12/13 pathway and consequent EGFR transactivation in vitro. These data demonstrate that a PA-PLA(1)α-LPA-P2Y5 axis regulates differentiation and maturation of hair follicles via a TACE-TGFα-EGFR pathway, thus underscoring the physiological importance of LPA-induced EGFR transactivation.


Assuntos
Receptores ErbB/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Lisofosfolipídeos/metabolismo , Fosfolipases A1/metabolismo , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Células Cultivadas , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Folículo Piloso/enzimologia , Humanos , Queratinócitos/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores Purinérgicos P2/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador alfa/metabolismo
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