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Inspired by the "natural camouflage" strategy, cell-based biomimetic drug delivery systems (BDDS) have shown great potential in cancer therapy. Red blood cell (RBC) delivery vehicles and red blood cell membrane (RBCm)-camouflaged vehicles were commonly used strategies for drug delivery. We prepared shikonin-encapsulated PLGA nanoparticles (PLGA/SK) with different surface charges to obtain both RBC delivery and RBCm-camouflaged PLGA NPs. The physicochemical properties, in vivo circulation and antitumor effects of these biomimetic preparations were studied. Since the positive PLGA NPs may affect the morphology and function of RBCs, the biomimetic preparations prepared by the negative PLGA NPs showed better in vitro stability. However, positive PLGA NP-based biomimetic preparations exhibited longer circulation time and higher tumor region accumulation, leading to stronger anti-tumor effects. Meanwhile, the RBC delivery PLGA(+) NPs possessed better in vitro cytotoxicity, longer circulation time and higher tumor accumulation than RBCm-camouflaged PLGA(+) NPs. Collectively, RBC delivery vehicles possessed more potential than RBCm-camouflaged vehicles on drug delivery for tumor treatment, especially with positive NPs-loaded.
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Neoplasias Colorrectales , Sistemas de Liberación de Medicamentos , Nanopartículas , Naftoquinonas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Naftoquinonas/química , Naftoquinonas/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Humanos , Ratones , Eritrocitos/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/química , Membrana Celular/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Tamaño de la Partícula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Membrana Eritrocítica/químicaRESUMEN
Combination therapy proven to be an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer. Currently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are combined with aromatase inhibitors (AIs) or selective estrogen receptor degraders (SERDs) as first-line therapy for advanced ER-positive breast cancer. Herein, a new family of quinoline scaffold SERDs was synthesized and evaluated in MCF-7 cells. Among them, compounds 18j and 24d exhibited remarkable MCF-7 inhibition, both alone and in combination with ribociclib (CDK4/6 inhibitor), in vitro and in vivo. Meanwhile, compounds 18j and 24d effectively degraded ER and inhibited ER downstream signaling pathways. Interestingly, compounds 18j and 24d induced endoplasmic reticulum stress (ERS) and triggered immunogenic cell death (ICD) via damage-associated molecular patterns (DAMPs) in MCF-7 cells. These findings highlight the immune-related and enhanced antiproliferative effects of oral SERDs in ER positive breast cancer treatment.
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Antineoplásicos , Neoplasias de la Mama , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Quinolinas , Receptores de Estrógenos , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Quinolinas/farmacología , Quinolinas/química , Quinolinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Receptores de Estrógenos/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Animales , Muerte Celular Inmunogénica/efectos de los fármacos , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Células MCF-7 , Ratones , Estrés del Retículo Endoplásmico/efectos de los fármacosRESUMEN
To assess the effectiveness and safety of combining Saccharomyces boulardii powder with triple therapy as a primary approach for eradicating H. pylori infection, a total of 144 patients who tested positive for H. pylori and diagnosed with non-ulcer dyspepsia underwent endoscopy at two national centers between June 2017 and March 2019 were included. The patients were categorized into three groups using a subsection randomization method and received initial H. pylori eradication treatments. Microbial composition, eradication rates, symptom alleviation, and adverse reactions were monitored on the 14th and 44th days post-treatment. According to PP analysis showed the eradication rates for the SRAC group was 75%, BRAC was 93.18% and RAC was 65.2%. Group BRAC exhibited a marginally higher eradication rate compared to other groups. However, patients receiving Saccharomyces boulardii treatment exhibited an overall reduction in initial dyspepsia symptoms by the end of the treatment period. When employed as a primary strategy, the combination of Saccharomyces boulardii powder with triple therapy displayed notable efficacy and smaller gastrointestinal side effects in eradicating initial H. pylori infections among non-ulcer dyspepsia patients. Moreover, this approach demonstrated advantages in alleviating symptoms, exhibited favorable tolerance, and maintained a high level of clinical safety.
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Quimioterapia Combinada , Dispepsia , Infecciones por Helicobacter , Helicobacter pylori , Probióticos , Saccharomyces boulardii , Humanos , Infecciones por Helicobacter/terapia , Infecciones por Helicobacter/tratamiento farmacológico , Masculino , Femenino , Helicobacter pylori/efectos de los fármacos , Persona de Mediana Edad , Probióticos/administración & dosificación , Probióticos/uso terapéutico , Dispepsia/microbiología , Dispepsia/terapia , Adulto , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Microbioma Gastrointestinal , Resultado del Tratamiento , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , Anciano , Amoxicilina/uso terapéutico , Amoxicilina/administración & dosificaciónRESUMEN
AIMS: Despite aggressive treatment, the recurrence of glioma is an inevitable occurrence, leading to unsatisfactory clinical outcomes. A plausible explanation for this phenomenon is the phenotypic alterations that glioma cells undergo aggressive therapies, such as TMZ-therapy. However, the underlying mechanisms behind these changes are not well understood. METHODS: The TMZ chemotherapy resistance model was employed to assess the expression of intercellular adhesion molecule-1 (ICAM1) in both in vitro and in vivo settings. The potential role of ICAM1 in regulating TMZ chemotherapy resistance was investigated through knockout and overexpression techniques. Furthermore, the mechanism underlying ICAM1-mediated TMZ chemotherapy resistance was examined using diverse molecular biological methods, and the lipid raft protein was subsequently isolated to investigate the cellular subcomponents where ICAM1 operates. RESULTS: Acquired TMZ resistant (TMZ-R) glioma models heightened production of intercellular adhesion molecule-1 (ICAM1) in TMZ-R glioma cells. Additionally, we observed a significant suppression of TMZ-R glioma proliferation upon inhibition of ICAM1, which was attributed to the enhanced intracellular accumulation of TMZ. Our findings provide evidence supporting the role of ICAM1, a proinflammatory marker, in promoting the expression of ABCB1 on the cell membrane of TMZ-resistant cells. We have elucidated the mechanistic pathway by which ICAM1 modulates phosphorylated moesin, leading to an increase in ABCB1 expression on the membrane. Furthermore, our research has revealed that the regulation of moesin by ICAM1 was instrumental in facilitating the assembly of ABCB1 exclusively on the lipid raft of the membrane. CONCLUSIONS: Our findings suggest that ICAM1 is an important mediator in TMZ-resistant gliomas and targeting ICAM1 may provide a new strategy for enhancing the efficacy of TMZ therapy against glioma.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioma , Molécula 1 de Adhesión Intercelular , Temozolomida , Resistencia a Antineoplásicos/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/genética , Glioma/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Humanos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Temozolomida/farmacología , Línea Celular Tumoral , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ratones , Microdominios de Membrana/metabolismo , Microdominios de Membrana/efectos de los fármacosRESUMEN
INTRODUCTION: The combination of a photosensitizer and indoleamine-2,3 dioxygenase (IDO) inhibitor provides a promising photoimmunotherapy (PIT) strategy for melanoma treatment. A dual drug delivery system offers a potential approach for optimizing the inhibitory effects of PIT on melanoma proliferation and metastasis. OBJECTIVE: To develop a dual drug delivery system based on PIT and to study its efficacy in inhibiting melanoma proliferation and metastasis. METHODS: We constructed a multifunctional nano-porphyrin material (P18-APBA-HA) using the photosensitizer-purpurin 18 (P18), hyaluronic acid (HA), and 4-(aminomethyl) phenylboronic acid (APBA). The resulting P18-APBA-HA was inserted into a phospholipid membrane and the IDO inhibitor epacadostat (EPA) was loaded into the internal phase to prepare a dual drug delivery system (Lip\EPA\P18-APBA-HA). Moreover, we also investigated its physicochemical properties, targeting, anti-tumor immunity, and anti-tumor proliferation and metastasis effects. RESULTS: The designed system utilized the pH sensitivity of borate ester to realize an enhanced-targeting strategy to facilitate the drug distribution in tumor lesions and efficient receptor-mediated cellular endocytosis. The intracellular release of EPA from Lip\EPA\P18-APBA-HA was triggered by thermal radiation, thereby inhibiting IDO activity in the tumor microenvironment, and promoting activation of the immune response. Intravenous administration of Lip\EPA\P18-APBA-HA effectively induced anti-tumor immunity by promoting dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression, and regulating cytokine secretion, to inhibit the proliferation of melanoma and lung metastasis. CONCLUSION: The proposed nano-drug delivery system holds promise as offers a promising strategy to enhance the inhibitory effects of the combination of EPA and P18 on melanoma proliferation and metastasis.
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Chitosan-based nanoparticles inevitably adsorb numerous proteins in the bloodstream, forming a protein corona that significantly influences their functionality. This study employed a pre-coated protein corona using cyclic Arg-Gly-Asp peptide (cRGD)-modified bovine serum albumin (BcR) to confer tumor-targeting capabilities on siVEGF-loaded chitosan-based nanoparticles (CsR/siVEGF NPs) and actively manipulated the serum protein corona composition to enhance their anti-tumor angiogenesis. Consequently, BcR effectively binds to the nanoparticles' surface, generating nanocarriers of appropriate size and stability that enhance the inhibition of endothelial cell proliferation, migration, invasion, and tube formation, as well as suppress tumor proliferation and angiogenesis in tumor-bearing nude mice. Proteomic analysis indicated a significant enrichment of serotransferrin, albumin, and proteasome subunit alpha type-1 in the protein corona of BcR-precoated NPs formed in the serum of tumor-bearing nude mice. Additionally, there was a decrease in proteins associated with complement activation, immunoglobulins, blood coagulation, and acute-phase responses. This modification resulted in an enhanced impact on anti-tumor angiogenesis, along with a reduction in opsonization and inflammatory responses. Therefore, pre-coating of nanoparticles with a functionalized albumin corona to manipulate the composition of serum protein corona emerges as an innovative approach to improve the delivery effectiveness of chitosan-based carriers for siVEGF, targeting the inhibition of tumor angiogenesis.
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Quitosano , Nanopartículas , Neovascularización Patológica , Corona de Proteínas , Albúmina Sérica Bovina , Quitosano/química , Animales , Nanopartículas/química , Ratones , Humanos , Corona de Proteínas/química , Albúmina Sérica Bovina/química , Neovascularización Patológica/tratamiento farmacológico , Ratones Desnudos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Proliferación Celular/efectos de los fármacos , Portadores de Fármacos/química , Bovinos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/química , AngiogénesisRESUMEN
USP2 and USP8 are crucial in the development and progression of breast cancer, primarily through the stabilization of protein substrates such as Her2 and ERα. The dual-target inhibitor ML364, targeting both USP2 and USP8, has garnered significant interest in recent research. In this study, we developed a series of ML364 derivatives using ligand-based drug design strategies. The standout compound, LLK203, demonstrated enhanced inhibitory activity, showing a 4-fold increase against USP2 and a 9-fold increase against USP8, compared to the parent molecule. In MCF-7 breast cancer cells, LLK203 effectively degraded key proteins involved in cancer progression and notably inhibited cell proliferation. Moreover, LLK203 exhibited potent in vivo efficacy in the 4T1 homograft model, while maintaining a low toxicity profile. These results underscore the potential of LLK203 as a promising dual-target inhibitor of USP2/USP8 for breast cancer treatment.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Células MCF-7 , Proliferación Celular , Ubiquitina Tiolesterasa , Endopeptidasas/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/farmacologíaRESUMEN
A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in colorectal cancer tumor tissues, which was further identified as a strong risk factor for colorectal cancer prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of colorectal cancer cell, as well as the epithelial-mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via the Akt/mTOR pathway, which triggered cAMP-responsive element-binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for ZEB1 transcription after binding to CREB1 half-site (GTCA) at ZEB1 promoter. As a key regulator of EMT, ZEB1, therefore, enhances migration and EMT process in colorectal cancer cells. We also found that HTR2B-specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process in both HCT116 cell tail-vein-injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models. IMPLICATIONS: These findings uncover a novel regulatory role of HTR2B signaling on colorectal cancer metastasis, which provide experimental evidences for potential HTR2B-targeted anti-colorectal cancer metastasis therapy.
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Neoplasias Colorrectales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Transición Epitelial-Mesenquimal , Receptor de Serotonina 5-HT2B , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Animales , Ratones , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2B/genética , Línea Celular Tumoral , Movimiento Celular , Metástasis de la Neoplasia , Transducción de Señal , Regulación Neoplásica de la Expresión Génica , Masculino , FemeninoRESUMEN
Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), and prolonged ER stress leads to cell apoptosis. Despite increasing research in this area, the underlying molecular mechanisms remain unclear. Here, we discover that ER stress upregulates the UPR signaling pathway while downregulating E2F target gene expression and inhibiting the G2/M phase transition. Prolonged ER stress decreases the mRNA levels of E2F2, which specifically regulates the expression of F-Box Protein 5(FBXO5), an F-box protein that functions as an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex. Depletion of FBXO5 results in increased ER stress-induced apoptosis and decreased expression of proteins related to PERK/IRE1α/ATF6 signaling. Overexpression of FBXO5 wild-type (not its ΔF-box mutant) alleviates apoptosis and the expression of the C/EBP Homologous Protein (CHOP)/ATF. Mechanistically, we find that FBXO5 directly binds to and promotes the ubiquitin-dependent degradation of RNF183, which acts as a ubiquitin E3 ligase in regulating ER stress-induced apoptosis. Reversal of the apoptosis defects caused by FBXO5 deficiency in colorectal cancer cells can be achieved by knocking down RNF183 in FBXO5-deficient cells. Functionally, we observed significant upregulation of FBXO5 in colon cancer tissues, and its silencing suppresses tumor occurrence in vivo. Therefore, our study highlights the critical role of the FBXO5/RNF183 axis in ER stress regulation and identifies a potential therapeutic target for colon cancer treatment.
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Neoplasias del Colon , Proteínas F-Box , Humanos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Endorribonucleasas/metabolismo , Estrés del Retículo Endoplásmico/genética , Respuesta de Proteína Desplegada , Ubiquitina/metabolismo , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Neoplasias del Colon/genética , Apoptosis/genética , Proteínas de Ciclo Celular/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Ischemic stroke still ranks as the most fatal disease worldwide. Blood-brain barrier (BBB) is a promising therapeutic target for protection. Brain microvascular endothelial cell is a core component of BBB, the barrier function maintenance of which can ameliorate ischemic injury and improve neurological deficit. Se-methyl L-selenocysteine (SeMC) has been shown to exert cardiovascular protection. However, the protection of SeMC against ischemic stroke remains to be elucidated. This research was designed to explore the protection of SeMC from the perspective of BBB protection. METHODS: To simulate cerebral ischemic injury, C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), and bEnd.3 was exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). After the intervention of SeMC, the barrier function and the expression of tight junction and ferroptosis-associated proteins were determined. For mechanism exploration, LY294002 (Akt inhibitor) was introduced both in vivo and in vitro. RESULTS: SeMC lessened the brain infarct volume and attenuated the leakage of BBB in mice. In vitro, SeMC improved cell viability and maintained the barrier function of bEnd.3 cells. The protection of SeMC was accompanied with ferroptosis inhibition and tight junction protein upregulation. Mechanism studies revealed that the effect of SeMC was reversed by LY294002, indicating that the protection of SeMC against ischemic stroke was mediated by the Akt signal pathway. CONCLUSION: These results suggested that SeMC exerted protection against ischemic stroke, which might be attributed to activating the Akt/GSK3ß signaling pathway and increasing the nuclear translocation of Nrf2 and ß-catenin, subsequently maintaining the integrity of BBB.
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Isquemia Encefálica , Ferroptosis , Accidente Cerebrovascular Isquémico , Daño por Reperfusión , Ratas , Ratones , Animales , Barrera Hematoencefálica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Endoteliales/metabolismo , Uniones Estrechas/metabolismo , Selenocisteína/metabolismo , Selenocisteína/farmacología , Selenocisteína/uso terapéutico , Regulación hacia Arriba , Ratas Sprague-Dawley , Ratones Endogámicos C57BL , Isquemia Encefálica/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Accidente Cerebrovascular Isquémico/metabolismoRESUMEN
Radiotherapy is widely used as the first-line treatment for nasopharyngeal carcinoma (NPC). However, the resistance of some patients to treatment lowers its clinical effectiveness. Compared to typical epithelial cells, NPC markedly lowers the Ras-association domain family 1A (RASSF1A) protein expression. RASSF1A overexpression sensitizes NPC cells to radiotherapy. Mechanistically, RASSF1A promotes the expression of Forkhead box O3a (FoxO3a) in the nucleus and inhibits the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway via binding to the Kelch-like ECH-associated protein 1 (Keap1) promoter. Through elevating intracellular ROS levels, RASSF1A overexpression inhibits the expression of thioredoxin reductase 1 (TXNRD1), a crucial Nrf2 target gene, and increases NPC sensitivity to radiation. Immunohistochemical staining of NPC tissue sections revealed that the expression of RASSF1A is negatively correlated with that of TXNRD1. The traditional Chinese medicine component andrographolide (AGP), which induces RASSF1A expression, increased the sensitivity of NPC cells to radiotherapy in vitro and in vivo. Our findings implied that RASSF1A increases the sensitivity of NPC to radiation by increasing FoxO3a expression in the nucleus, inhibiting the Nrf2/TXNRD1 signaling pathway, and elevating intracellular ROS levels. AGP targets RASSF1A and may be a promising adjuvant sensitizer for enhancing radiosensitivity in NPC.
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Neoplasias Nasofaríngeas , Tiorredoxina Reductasa 1 , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/metabolismo , Tiorredoxina Reductasa 1/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2 , Neoplasias Nasofaríngeas/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Tolerancia a Radiación , Línea Celular TumoralRESUMEN
Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.
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BACKGROUND: MYCN amplification as a common genetic alteration that correlates with a poor prognosis for neuroblastoma (NB) patients. However, given the challenge of directly targeting MYCN, indirect strategies to modulate MYCN by interfering with its cofactors are attractive in NB treatment. Although cyclin B1 interacting protein 1 (CCNB1IP1) has been found to be upregulated in MYCN-driven mouse NB tissues, its regulation with MYCN and collaboration in driving the biological behaviour of NB remains unknown. METHODS: To evaluate the expression and clinical significance of CCNB1IP1 in NB patients, public datasets, clinical NB samples and cell lines were explored. MTT, EdU incorporation, colony and tumour sphere formation assays, and a mouse xenograft tumour model were utilized to examine the biological function of CCNB1IP1. The reciprocal manipulation of CCNB1IP1 and MYCN and the underlying mechanisms involved were investigated by gain- and loss-of-function approaches, dual-luciferase assay, chromatin immunoprecipitation (CHIP) and co-immunoprecipitation (Co-IP) experiments. RESULTS: CCNB1IP1 was upregulated in MYCN-amplified (MYCN-AM) NB cell lines and patients-derived tumour tissues, which was associated with poor prognosis. Phenotypic studies revealed that CCNB1IP1 facilitated the proliferation and tumourigenicity of NB cells in cooperation with MYCN in vitro and in vivo. Mechanistically, MYCN directly mediates the transcription of CCNB1IP1, which in turn attenuated the ubiquitination and degradation of MYCN protein, thus enhancing CCNB1IP1-MYCN cooperativity. Moreover, CCNB1IP1 competed with F box/WD-40 domain protein 7 (FBXW7) for MYCN binding and enabled MYCN-mediated tumourigenesis in a C-terminal domain-dependent manner. CONCLUSIONS: Our study revealed a previously uncharacterized mechanism of CCNB1IP1-mediated MYCN protein stability and will provide new prospects for precise treatment of MYCN-AM NB based on MYCN-CCNB1IP1 interaction.
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Transformación Celular Neoplásica , Neuroblastoma , Humanos , Animales , Ratones , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Línea Celular , Neuroblastoma/patología , Carcinogénesis , Ubiquitinación/genéticaRESUMEN
The regimens on colorectal cancer (CRC) are clinically limited due to the ignorance of tumor-supportive microenvironments. To combine the therapeutic effects on both tumor cells growth and immunosuppressive tumor microenvironments (TME), we propose the artesunate (AS) and chloroquine (CQ) combination and develop a poly (d,l-lactide-co-glycolide) (PLGA)-based biomimetic nanoparticle for dual-targeting delivery of the drug combination. Hydroxymethyl phenylboronic acid conjugated PLGA (HPA) is synthesized to form a reactive oxygen species (ROS)-sensitive core of biomimetic nanoparticles. A mannose-modified erythrocyte membrane (Man-EM) obtained by a novel surface modification method is cloaked on the AS and CQ-loaded HPA core to receive a biomimetic nanoparticle-HPA/AS/CQ@Man-EM. It holds a strong promise in inhibiting the proliferation of CRC tumor cells and reversing the phenotypes of TAMs via targeting both tumor cells and M2-like tumor-associated macrophages (TAMs). Verifying in an orthotopic CRC mouse model, the biomimetic nanoparticles showed improved accumulation at tumor tissues and effectively suppressed the tumor growth via both inhibition of tumor cell growth and repolarization of TAMs. Notably, unbalanced distribution to the tumor cells and TAMs is the key to realize the remarkable anti-tumor effects. This work proposed an effective biomimetic nanocarrier for the CRC treatment.
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Neoplasias Colorrectales , Nanopartículas , Animales , Ratones , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Artesunato/farmacología , Artesunato/uso terapéutico , Macrófagos Asociados a Tumores/patología , Cloroquina/farmacología , Biomimética , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Microambiente TumoralRESUMEN
Atherosclerosis (AS) is a systemic disease characterized by lipid deposition in the blood vessel wall that urgently requires effective and safe therapeutic drugs for long-term treatment. An essential oil monomer-1,8-cineole (CIN) with ameliorative effects on vascular injuries has considerable potential for preventing the progression of AS because of its antioxidant, anti-inflammation, and cholesterol regulatory effects. However, the high volatility and instability of CIN result in low oral bioavailability and a short half-life, thereby limiting its clinical application. We formulated a nanoemulsion using a polysaccharide-protein/protein complex (dextran-bovine serum albumin/protamine, DEX5k-BSA/PTM) as an emulsifier, with vitamin B12 (VB12) as the ligand to facilitate the transportation across the small intestine. An emulsion preparation method using a microjet followed by ultraviolet irradiation was developed to obtain the CIN-loaded oral nanoemulsion CIN@DEX5k-BSA/PTM/VB12. The nanoemulsion improved the stability of CIN both in vitro and in vivo, prolonged the retention time in the gastrointestinal tract (GIT), and enhanced the permeability across the mucus layer and intestinal epithelial cells to increase oral bioavailability and plaque accumulation of CIN. Validated in an AS mouse model, CIN@DEX5k-BSA/PTM/VB12 achieved prominent therapeutic efficacy combating AS. This study highlights the advantages of DEX5k-BSA/PTM and VB12 in the development of nanoemulsions for CIN and provides a promising oral nanoplatform for the delivery of essential oils.
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Aterosclerosis , Polisacáridos , Ratones , Animales , Eucaliptol , Preparaciones Farmacéuticas , Disponibilidad Biológica , Polisacáridos/uso terapéutico , Emulsiones , Administración OralRESUMEN
Prostate cancer (PC) is one of the most prevalent cancers in men worldwide, and androgen receptor (AR) is a well-validated drug target for the treatment of PC. However, PC often exhibits resistance to AR antagonists over time. Thus, it is urgent to identify novel and effective drugs for PC treatment. A series of novel thiohydantoin based AR antagonists with efficient degradation against AR were designed, synthesized, and evaluated. Based on our previous SAR and further structural optimization, a tool molecule 26h was discovered with dual mechanisms including improved antagonistic activity and potent degradation (AR-fl and AR-V7). Moreover, 26h can also effectively block AR nuclear translocation and inhibit AR/AR-V7 heterodimerization, thereby inhibiting downstream gene transcription. Importantly, 26h displayed potent robust efficacy in LNCaP (TGI: 70.70%) and 22Rv1 (TGI: 78.89%) xenograft models. This provides new design strategies and advantageous potential compounds for the treatment of prostate cancer.
Asunto(s)
Neoplasias de la Próstata , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/metabolismo , Tiohidantoínas/química , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Antagonistas de Receptores Androgénicos/química , Línea Celular Tumoral , Antagonistas de Andrógenos/farmacología , Proliferación CelularRESUMEN
Cancer immunotherapy has opened a new landscape in cancer treatment, however, the poor specificity and resistance of most targeted therapeutics have limited their therapeutic efficacy. In recent years, the role of CAFs in immune regulation has been increasingly noted as more evidence has been uncovered regarding the link between cancer-associated fibroblasts (CAFs) and the evolutionary process of tumor progression. CAFs interact with immune cells to shape the tumor immune microenvironment (TIME) that favors malignant tumor progression, a crosstalk process that leads to the failure of cancer immunotherapies. In this review, we outline recent advances in the immunosuppressive function of CAFs, highlight the mechanisms of CAFs-immune cell interactions, and discuss current CAF-targeted therapeutic strategies for future study.
RESUMEN
Although endocrine therapies involving pharmaceuticals, such as tamoxifen and aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first generation selective estrogen receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine-substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clinical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure-activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent pharmacokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Flúor/uso terapéutico , Receptor alfa de Estrógeno/metabolismo , Antagonistas de Estrógenos/farmacologíaRESUMEN
The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.