Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.126
Filtrar
Más filtros

Intervalo de año de publicación
1.
J Ethnopharmacol ; 330: 118195, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38641080

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is a frequently used herbal medicine worldwide, and is used to treat cough, hepatitis, cancer and influenza in clinical practice of traditional Chinese medicine. Modern pharmacological studies indicate that prenylated flavonoids play an important role in the anti-tumor activity of licorice, especially the tumors in stomach, lung, colon and liver. Wighteone is one of the main prenylated flavonoids in licorice, and its possible effect and target against colorectal cancer have not been investigated. AIM OF THE STUDY: This study aimed to investigate the anti-colorectal cancer effect and underlying mechanism of wighteone. MATERIALS AND METHODS: SW480 human colorectal cancer cells were used to evaluate the in vitro anti-colorectal cancer activity and Akt regulation effect of wighteone by flow cytometry, phosphoproteomic and Western blot analysis. Surface plasmon resonance (SPR) assay, molecular docking and dynamics simulation, and kinase activity assay were used to investigate the direct interaction between wighteone and Akt. A nude mouse xenograft model with SW480 cells was used to verify the in vivo anti-colorectal cancer activity of wighteone. RESULTS: Wighteone inhibited phosphorylation of Akt and its downstream kinases in SW480 cells, which led to a reduction in cell viability. Wighteone had direct interaction with both PH and kinase domains of Akt, which locked Akt in a "closed" conformation with allosteric inhibition, and Gln79, Tyr272, Arg273 and Lys297 played the most critical role due to their hydrogen bond and hydrophobic interactions with wighteone. Based on Akt overexpression or activation in SW480 cells, further mechanistic studies suggested that wighteone-induced Akt inhibition led to cycle arrest, apoptosis and autophagic death of SW480 cells. Moreover, wighteone exerted in vivo anti-colorectal cancer effect and Akt inhibition activity in the nude mouse xenograft model. CONCLUSION: Wighteone could inhibit growth of SW480 cells through allosteric inhibition of Akt, which led to cell cycle arrest, apoptosis and autophagic death. The results contributed to understanding of the anti-tumor mechanism of licorice, and also provided a rationale to design novel Akt allosteric inhibitors for the treatment of colorectal cancer.


Asunto(s)
Antineoplásicos Fitogénicos , Neoplasias Colorrectales , Flavonoides , Glycyrrhiza , Proteínas Proto-Oncogénicas c-akt , Animales , Humanos , Masculino , Ratones , Regulación Alostérica/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/uso terapéutico , Flavonoides/química , Glycyrrhiza/química , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
J Control Release ; 370: 168-181, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38643936

RESUMEN

The high prevalence and severity of hepatocellular carcinoma (HCC) present a significant menace to human health. Despite the significant advancements in nanotechnology-driven antineoplastic agents, there remains a conspicuous gap in the development of targeted chemotherapeutic agents specifically designed for HCC. Consequently, there is an urgent need to explore potent drug delivery systems for effective HCC treatment. Here we have exploited the interplay between HCC and adipocyte to engineer a hybrid adipocyte-derived exosome platform, serving as a versatile vehicle to specifically target HCC and exsert potent antitumor effect. A lipid-like prodrug of docetaxel (DSTG) with a reactive oxygen species (ROS)-cleavable linker, and a lipid-conjugated photosensitizer (PPLA), spontaneously co-assemble into nanoparticles, functioning as the lipid cores of the hybrid exosomes (HEMPs and NEMPs). These nanoparticles are further encapsuled within adipocyte-derived exosome membranes, enhancing their affinity towards HCC cancer cells. As such, cancer cell uptakes of hybrid exosomes are increased up to 5.73-fold compared to lipid core nanoparticles. Our in vitro and in vivo experiments have demonstrated that HEMPs not only enhance the bioactivity of the prodrug and extend its circulation in the bloodstream but also effectively inhibit tumor growth by selectively targeting hepatocellular carcinoma tumor cells. Self-facilitated synergistic drug release subsequently promoting antitumor efficacy, inducing significant inhibition of tumor growth with minimal side effects. Our findings herald a promising direction for the development of targeted HCC therapeutics.


Asunto(s)
Adipocitos , Antineoplásicos , Carcinoma Hepatocelular , Docetaxel , Exosomas , Neoplasias Hepáticas , Nanopartículas , Exosomas/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Animales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Humanos , Docetaxel/administración & dosificación , Docetaxel/farmacología , Docetaxel/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Adipocitos/efectos de los fármacos , Nanopartículas/química , Nanopartículas/administración & dosificación , Profármacos/administración & dosificación , Profármacos/uso terapéutico , Línea Celular Tumoral , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Ratones Desnudos , Fototerapia/métodos , Sistemas de Liberación de Medicamentos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos BALB C
3.
Phytomedicine ; 129: 155631, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38640858

RESUMEN

BACKGROUND: The utilization of Chinese medicine as an adjunctive therapy for cancer has recently gained significant attention. Ferroptosis, a newly regulated cell death process depending on the ferrous ions, has been proved to be participated in glioma stem cells inactivation. PURPOSE: We aim to study whether ginsenoside Rg5 exerted inhibitory effects on crucial aspects of glioma stem cells, including cell viability, tumor initiation, invasion, self-renewal ability, neurosphere formation, and stemness. METHODS: Through comprehensive sequencing analysis, we identified a compelling association between ginsenoside Rg5 and the ferroptosis pathway, which was further validated through subsequent experiments demonstrating its ability to activate this pathway. RESULTS: To elucidate the precise molecular targets affected by ginsenoside Rg5 in gliomas, we conducted an intersection analysis between differentially expressed genes obtained from sequencing and a database-predicted list of transcription factors and potential targets of ginsenoside Rg5. This rigorous approach led us to unequivocally confirm NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1) as a direct target of ginsenoside Rg5, a finding consistently supported by subsequent experimental investigations. Moreover, we uncovered NR3C1's capacity to transcriptionally regulate ferroptosis -related genes HSPB1 and NCOA4. Strikingly, ginsenoside Rg5 induced notable alterations in the expression levels of both HSPB1 (Heat Shock Protein Family B Member 1) and NCOA4 (Nuclear Receptor Coactivator 4). Finally, our intracranial xenograft assays served to reaffirm the inhibitory effect of ginsenoside Rg5 on the malignant progression of glioblastoma. CONCLUSION: These collective findings strongly suggest that ginsenoside Rg5 hampers glioblastoma progression by activating ferroptosis through NR3C1, which subsequently modulates HSPB1 and NCOA4. Importantly, this novel therapeutic direction holds promise for advancing the treatment of glioblastoma.


Asunto(s)
Ferroptosis , Ginsenósidos , Glioblastoma , Ginsenósidos/farmacología , Ferroptosis/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Animales , Línea Celular Tumoral , Coactivadores de Receptor Nuclear/metabolismo , Ratones , Ratones Desnudos , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico
4.
J Mater Chem B ; 12(16): 4039-4052, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38591157

RESUMEN

Clear cell renal cell carcinoma (ccRCC) is a disease with high incidence and poor prognosis. The conventional treatment involves radiotherapy and chemotherapy, but chemotherapeutic agents are often associated with side effects, i.e., cytotoxicity to nontumor cells. Therefore, there is an urgent need for the development of novel therapeutic strategies for ccRCC. We synthesized spherical P/TiO2 nanoparticles (P/TiO2 NPs) by vaporization phosphorization (VP). X-ray photoelectron spectroscopy (XPS) and ultraviolet-visible diffuse reflectance spectroscopy (UV-Vis DRS) analyses confirmed that the anatase TiO2 surface was successfully doped with phosphorus and produced a large number of oxygen vacancies (OV). Serving as a photosensitizer, P/TiO2 NPs not only extended the photoresponse range to the near-infrared II region (NIR II) but also introduced a donor energy level lower than the TiO2 conduction band, narrowing the band gap, which could facilitate the migration of photogenerated charges and trigger the synergistic treatment of photodynamic therapy (PDT) and photothermal therapy (PTT). During NIR irradiation in vitro, the P/TiO2 NPs generated local heat and various oxygen radicals, including 1O2, ˙O2-, H2O2, and ˙OH, which damaged the ccRCC cells. In vivo, administration of the P/TiO2 NPs + NIR reduced the tumor volume by 80%, and had the potential to inhibit tumor metastasis by suppressing intratumor neoangiogenesis. The P/TiO2 NPs showed superior safety and efficacy relative to the conventional chemotherapeutic agent used in ccRCC treatment. This study introduced an innovative paradigm for renal cancer treatment, highlighting the potential of P/TiO2 NPs as safe and effective nanomaterials and presenting a compelling new option for clinical applications in anticancer therapy.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Nanocompuestos , Fósforo , Fotoquimioterapia , Terapia Fototérmica , Titanio , Titanio/química , Titanio/farmacología , Fósforo/química , Humanos , Animales , Nanocompuestos/química , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/terapia , Ratones , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales , Tamaño de la Partícula , Línea Celular Tumoral
5.
Zhongguo Zhong Yao Za Zhi ; 49(4): 1044-1051, 2024 Feb.
Artículo en Chino | MEDLINE | ID: mdl-38621911

RESUMEN

The animal and cell models were used in this study to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in inhibiting colon cancer progression and enhancing the efficacy of 5-fluorouracil(5-FU) by regulating hypoxia-inducible factors and tumor stem cells. The animal model was established by subcutaneous transplantation of colon cancer HCT116 cells in nude mice, and 24 successfully modeled mice were randomized into model, 5-FU, HQEZ, and 5-FU+HQEZ groups. The tumor volume was measured every two days. Western blot was employed to measure the protein levels of epidermal growth factor receptor(EGFR), dihydropyrimidine dehydrogenase(DPYD), and thymidylate synthase(TYMS), the key targets of the hypoxic core region, as well as the hypoxia-inducible factors HIF-1α and HIF-2α and the cancer stem cell surface marker CD133 and SRY-box transcription factor 2(SOX2). The results of animal experiments showed that HQEZ slowed down the tumor growth and significantly increased the tumor inhibition rate of 5-FU. Compared with the model group, HQEZ significantly down-regulated the protein levels of EGFR and DPYD, and 5-FU+HQEZ significantly down-regulated the protein levels of EGFR and TYMS in tumors. Compared with the model group, HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, SOX2, and CD133 in the hypoxic core region. Compared with the 5-FU group, 5-FU+HQEZ lowered the protein levels of HIF-1α, HIF-2α, and SOX2. The cell experiments showed that the protein le-vels of HIF-1α and HIF-2α in HCT116 cells elevated significantly after low oxygen treatment. Compared with 5-FU(1.38 µmol·L~(-1)) alone, HQEZ(40 mg·mL~(-1)) and 5-FU+HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, and TYMS. In conclusion, HQEZ can inhibit the expression of hypoxia-responsive molecules in colon cancer cells and reduce the properties of cancer stem cells, thereby enhancing the therapeutic effect of 5-FU on colon cancer.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Neoplasias del Colon , Ratones , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ratones Desnudos , Fluorouracilo/farmacología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Hipoxia , Receptores ErbB , Células Madre Neoplásicas , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Línea Celular Tumoral
6.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167152, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38582012

RESUMEN

Intrahepatic cholangiocarcinoma (ICC) is a kind of hepatobiliary tumor that is increasing in incidence and mortality. The gut microbiota plays a role in the onset and progression of cancer, however, the specific mechanism by which the gut microbiota acts on ICC remains unclear. In this study, feces and plasma from healthy controls and ICC patients were collected for 16S rRNA sequencing or metabolomics analysis. Gut microbiota analysis showed that gut microbiota abundance and biodiversity were altered in ICC patients compared with controls. Plasma metabolism analysis showed that the metabolite glutamine content of the ICC patient was significantly higher than that of the controls. KEGG pathway analysis showed that glutamine plays a vital role in ICC. In addition, the use of antibiotics in ICC animals further confirmed that changes in gut microbiota affect changes in glutamine. Further experiments showed that supplementation with glutamine inhibited ferroptosis and downregulated ALK5 and NOX1 expression in HuCCT1 cells. ALK5 overexpression or NOX1 overexpression increased NOX1, p53, PTGS2, ACSL4, LPCAT3, ROS, MDA and Fe2+ and decreased FTH1, SLC7A11 and GSH. Knockdown of NOX1 suppressed FIN56-induced ferroptosis. In vivo, supplementation with glutamine promoted tumor growth. Overexpression of ALK5 repressed tumor growth and induced ferroptosis in nude mice, which could be reversed by the addition of glutamine. Our results suggested that the gut microbiota altered glutamine metabolism to inhibit ferroptosis in ICC by regulating the ALK5/NOX1 axis.


Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Ferroptosis , Microbioma Gastrointestinal , Glutamina , NADPH Oxidasa 1 , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , Colangiocarcinoma/microbiología , Colangiocarcinoma/tratamiento farmacológico , Ferroptosis/efectos de los fármacos , Humanos , Glutamina/metabolismo , NADPH Oxidasa 1/metabolismo , NADPH Oxidasa 1/genética , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/microbiología , Ratones , Masculino , Línea Celular Tumoral , Receptores de Activinas Tipo I/metabolismo , Receptores de Activinas Tipo I/genética , Ratones Desnudos , Femenino , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptor Tipo I de Factor de Crecimiento Transformador beta
7.
J Ethnopharmacol ; 330: 118228, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38643863

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Prostate cancer (PCa) is the most common malignancy of the male genitourinary system and currently lacks effective treatment. Semen Impatientis, the dried ripe seed of Impatiens balsamina L., is described by the Chinese Pharmacopoeia as a traditional Chinese medicine (TCM) and is used in clinical practice to treat tumors, abdominal masses, etc. In our previous study, the ethyl acetate extracts of Semen Impatientis (EAESI) was demonstrated to be the most effective extract against PCa among various extracts. However, the biological effects of EAESI against PCa in vivo and the specific antitumor mechanisms involved remain unknown. AIM OF THE STUDY: In this study, we aimed to investigate the antitumor effect of EAESI on PCa in vitro and in vivo by performing network pharmacology analysis, transcriptomic analysis, and experiments to explore and verify the underlying mechanisms involved. MATERIALS AND METHODS: The antitumor effect of EAESI on PCa in vitro and in vivo was investigated via CCK-8, EdU, flow cytometry, and wound healing assays and xenograft tumor models. Network pharmacology analysis and transcriptomic analysis were employed to explore the underlying mechanism of EAESI against PCa. Activating transcription factor 3 (ATF3) and androgen receptor (AR) were confirmed to be the targets of EAESI against PCa by RT‒qPCR, western blotting, and rescue assays. In addition, the interaction between ATF3 and AR was assessed by coimmunoprecipitation, immunofluorescence, and nuclear-cytoplasmic separation assays. RESULTS: EAESI decreased cell viability, inhibited cell proliferation and migration, and induced apoptosis in AR+ and AR- PCa cells. Moreover, EAESI suppressed the growth of xenograft tumors in vivo. Network pharmacology analysis revealed that the hub targets of EAESI against PCa included AR, AKT1, TP53, and CCND1. Transcriptomic analysis indicated that activating transcription factor 3 (ATF3) was the most likely critical target of EAESI. EAESI downregulated AR expression and decreased the transcriptional activity of AR through ATF3 in AR+ PCa cells; and EAESI promoted the expression of ATF3 and exerted its antitumor effect via ATF3 in AR+ and AR- PCa cells. CONCLUSIONS: EAESI exerts good antitumor effects on PCa both in vitro and in vivo, and ATF3 and AR are the critical targets through which EAESI exerts antitumor effects on AR+ and AR- PCa cells.


Asunto(s)
Acetatos , Factor de Transcripción Activador 3 , Ratones Desnudos , Farmacología en Red , Neoplasias de la Próstata , Receptores Androgénicos , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Animales , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Acetatos/química , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Ratones , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Transcriptoma/efectos de los fármacos , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos
8.
BMC Complement Med Ther ; 24(1): 174, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664638

RESUMEN

Liver cancer is a common malignant tumor worldwide, traditional Chinese medicine is one of the treatment measures for liver cancer because of its good anti-tumor effects and fewer toxic side effects. Ginsenoside CK (CK) is an active component of ginseng. This study explored the mechanism by which CK induced ferroptosis in liver cancer cells. We found that CK inhibited the proliferation of HepG2 and SK-Hep-1 cells, induced ferroptosis of cells. Ferrostatin-1, an ferroptosis inhibitor, was used to verify the role of CK in inducing ferroptosis of liver cancer cells. Network pharmacological analysis identified the FOXO pathway as a potential mechanism of CK, and western blot showed that CK inhibited p-FOXO1. In cells treated with the FOXO1 inhibitor AS1842856, further verify the involvement of the FOXO pathway in regulating CK-induced ferroptosis in HepG2 and SK-Hep-1 cells. A HepG2 cell-transplanted tumor model was established in nude mice, and CK inhibited the growth of transplanted tumors in nude mice, p-FOXO1 was decreased in tumor tissues, and SLC7A11 and GPX4 expressions were also down-regulated after CK treatment. These findings suggested that CK induces ferroptosis in liver cancer cells by inhibiting FOXO1 phosphorylation and activating the FOXO signaling pathway, thus playing an antitumor role.


Asunto(s)
Ferroptosis , Ginsenósidos , Neoplasias Hepáticas , Ratones Desnudos , Transducción de Señal , Ferroptosis/efectos de los fármacos , Ginsenósidos/farmacología , Humanos , Animales , Ratones , Neoplasias Hepáticas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Células Hep G2 , Ratones Endogámicos BALB C , Proteína Forkhead Box O1/metabolismo , Línea Celular Tumoral
9.
Chin J Nat Med ; 22(4): 318-328, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38658095

RESUMEN

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1ß inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.


Asunto(s)
Antraquinonas , Proliferación Celular , Neoplasias Colorrectales , Quinasas Similares a Doblecortina , Péptidos y Proteínas de Señalización Intracelular , Proteínas Serina-Treonina Quinasas , Factor de Transcripción STAT3 , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Antraquinonas/farmacología , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos
10.
J Nanobiotechnology ; 22(1): 202, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658952

RESUMEN

Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.


Asunto(s)
Autofagia , Neoplasias Colorrectales , Reposicionamiento de Medicamentos , Ivermectina , Nanopartículas , Autofagia/efectos de los fármacos , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Humanos , Ratones , Nanopartículas/química , Ivermectina/farmacología , Ivermectina/química , Línea Celular Tumoral , Indoles/química , Indoles/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Fotoquimioterapia/métodos , Antineoplásicos/farmacología , Antineoplásicos/química , Fototerapia/métodos , Ácido Hialurónico/química , Hidroxicloroquina/farmacología , Hidroxicloroquina/química , Terapia Fototérmica/métodos
11.
Phytomedicine ; 128: 155497, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38640855

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is a significant public health issue, ranking as one of the predominant cancer types globally in terms of incidence. Intriguingly, Arenobufagin (Are), a compound extracted from toad venom, has demonstrated the potential to inhibit tumor growth effectively. PURPOSE: This study aimed to explore Are's molecular targets and unravel its antitumor mechanism in CRC. Specifically, we were interested in its impact on immune checkpoint modulation and correlations with HSP90ß-STAT3-PD-L1 axis activity. METHODS: We investigated the in vivo antitumor effects of Are by constructing a colorectalcancer subcutaneous xenograft mouse model. Subsequently, we employed single-cell multi-omics technology to study the potential mechanism by which Are inhibits CRC. Utilizing target-responsive accessibility profiling (TRAP) technology, we identified heatshock protein 90ß (HSP90ß) as the direct target of Are, and confirmed this through a microscale thermophoresis experiment (MST). Further downstream mechanisms were explored through techniques such as co-immunoprecipitation, Western blotting, qPCR, and immunofluorescence. Concurrently, we arrived at the same research conclusion at the organoid level by co-cultivating with immune cells. RESULTS: We observed that Are inhibits PD-Ll expression in CRC tumor xenografts at low concentrations. Moreover, TRAP revealed that HSP90ß's accessibility significantly decreased upon Are binding. We demonstrated a decrease in the activity of the HSP90ß-STAT3-PD-Ll axis following low-concentration Are treatment in vivo. The PDO analysis showed improved enrichment of lymphocytes, particularly T cells, on the PDOs following Are treatment. CONCLUSION: Contrary to previous research focusing on the direct cytotoxicity of Are towards tumor cells, our findings indicate that it can also inhibit tumor growth at lower concentrations through the modulation of immune checkpoints. This study unveils a novel anti-tumor mechanism of Are and stimulates contemplation on the dose-response relationship of natural products, which is beneficial for the clinical translational application of Are.


Asunto(s)
Bufanólidos , Neoplasias Colorrectales , Proteínas HSP90 de Choque Térmico , Factor de Transcripción STAT3 , Ensayos Antitumor por Modelo de Xenoinjerto , Bufanólidos/farmacología , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Ratones , Factor de Transcripción STAT3/metabolismo , Linfocitos T/efectos de los fármacos , Línea Celular Tumoral , Antígeno B7-H1 , Ratones Desnudos , Ratones Endogámicos BALB C , Venenos de Anfibios/farmacología , Femenino
12.
Acta Biochim Biophys Sin (Shanghai) ; 56(5): 763-775, 2024 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-38516703

RESUMEN

Traditional Chinese medicine (TCM) has been used to treat triple-negative breast cancer (TNBC), a breast cancer subtype with poor prognosis. Clinical studies have verified that the Sanyingfang formula (SYF), a TCM prescription, has obvious effects on inhibiting breast cancer recurrence and metastasis, prolonging patient survival, and reducing clinical symptoms. However, its active ingredients and molecular mechanisms are still unclear. In this study, the active ingredients of each herbal medicine composing SYF and their target proteins are obtained from the Traditional Chinese Medicine Systems Pharmacology database. Breast cancer-related genes are obtained from the GeneCards database. Major targets and pathways related to SYF treatment in breast cancer are identified by analyzing the above data. By conducting molecular docking analysis, we find that the active ingredients quercetin and luteolin bind well to the key targets KDR1, PPARG, SOD1, and VCAM1. In vitro experiments verify that SYF can reduce the proliferation, migration, and invasion ability of TNBC cells. Using a TNBC xenograft mouse model, we show that SYF could delay tumor growth and effectively inhibit the occurrence of breast cancer lung metastasis in vivo. PPARG, SOD1, KDR1, and VCAM1 are all regulated by SYF and may play important roles in SYF-mediated inhibition of TNBC recurrence and metastasis.


Asunto(s)
Proliferación Celular , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/química , Humanos , Animales , Femenino , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Farmacología en Red , Movimiento Celular/efectos de los fármacos , Ratones Desnudos , Luteolina/farmacología , Luteolina/uso terapéutico , Ratones Endogámicos BALB C , Quercetina/farmacología , Quercetina/química , Medicina Tradicional China , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos
13.
Phytomedicine ; 129: 155552, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38552378

RESUMEN

BACKGROUND: Studies have shown that phenylethanoid glycosides (PhGs) have multiple pharmacological effects such as anti-inflammatory, hepatoprotective or neuroprotective functions, whereas their anti-tumor effects are rarely studied. Tubuloside B (Tub B) is a PhG isolated from Cistanche deserticola, a traditional Chinese medicine. To date, there is a lack of comprehensive research regarding the biological activity of Tub B. PURPOSE: The subject of the current study was to investigate the anti-hepatocellular carcinoma (HCC) cell activity and the underlying mechanism of Tub B. METHODS: We evaluated the in vitro anti-migratory effect of Tub B by scratch and transwell assays. RNA-seq was employed to identify the differential genes by Tub B. Besides, the functional mechanism of Tub B was investigated by distinct molecular biology techniques including immunofluorescent staining, quantitative PCR, as well as western blot analysis. Subsequently, we utilized Hep3B cells for in vivo metastasis assays through spleen injection and evaluated the anti-migratory effect of Tub B in hepatocellular carcinoma (HCC). RESULTS: Tub B exhibited in vitro and in vivo inhibition of HCC cell migration. Tub B decreased the expression of transcriptional target genes downstream of the Hippo pathway, including CTGF, CYR61, and N-cadherin as determined by RNA-seq. Furthermore, mechanistic studies confirmed that Tub B increased phosphorylation of YAP at S127, which contributes to YAP cytoplasmic localization. Additionally, overexpression of YAP abrogated Tub B-induced inhibition of HCC migration and the mRNA levels of CTGF, CYR61, and N-cadherin. CONCLUSIONS: Taken together, these results illustrated that Tub B demonstrated great potential in inhibiting migration of HCC, and a portion of its impact can be attributed to the modulation of the Hippo-YAP pathway.


Asunto(s)
Carcinoma Hepatocelular , Movimiento Celular , Cistanche , Vía de Señalización Hippo , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Humanos , Movimiento Celular/efectos de los fármacos , Cistanche/química , Animales , Línea Celular Tumoral , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/metabolismo , Glicósidos/farmacología , Proteínas Señalizadoras YAP , Antineoplásicos Fitogénicos/farmacología , Transducción de Señal/efectos de los fármacos , Ratones Desnudos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ratones , Ratones Endogámicos BALB C , Masculino
14.
Adv Mater ; 36(27): e2401009, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38548296

RESUMEN

Tissue engineering and electrotherapy are two promising methods to promote tissue repair. However, their integration remains an underexplored area, because their requirements on devices are usually distinct. Triboelectric nanogenerators (TENGs) have shown great potential to develop self-powered devices. However, due to their susceptibility to moisture, TENGs have to be encapsulated in vivo. Therefore, existing TENGs cannot be employed as tissue engineering scaffolds, which require direct interaction with surrounding cells. Here, the concept of triboelectric scaffolds (TESs) is proposed. Poly(glycerol sebacate), a biodegradable and relatively hydrophobic elastomer, is selected as the matrix of TESs. Each hydrophobic micropore in multi-hierarchical porous TESs efficiently serves as a moisture-resistant working unit of TENGs. Integration of tons of micropores ensures the electrotherapy ability of TESs in vivo without encapsulation. Originally hydrophobic TESs are degraded by surface erosion and transformed into hydrophilic surfaces, facilitating their role as tissue engineering scaffolds. Notably, TESs seeded with chondrocytes obtain dense and large matured cartilages after subcutaneous implantation in nude mice. Importantly, rabbits with osteochondral defects receiving TES implantation show favorable hyaline cartilage regeneration and complete cartilage healing. This work provides a promising electronic biomedical device and will inspire a series of new in vivo applications.


Asunto(s)
Decanoatos , Interacciones Hidrofóbicas e Hidrofílicas , Polímeros , Regeneración , Ingeniería de Tejidos , Andamios del Tejido , Andamios del Tejido/química , Animales , Porosidad , Conejos , Ingeniería de Tejidos/métodos , Decanoatos/química , Polímeros/química , Ratones , Glicerol/química , Glicerol/análogos & derivados , Cartílago/fisiología , Condrocitos/citología , Ratones Desnudos , Materiales Biocompatibles/química
15.
J Am Chem Soc ; 146(12): 8567-8575, 2024 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-38489761

RESUMEN

Ferroptosis as a promising method of cancer treatment heavily relies on the intracellular iron ion level. Herein, a new iron-supplement nanodrug was developed by conjugating transferrin-homing peptide T10 on the surface of cross-linked lipoic acid vesicles (T10@cLAV), which could hijack blood transferrin (Tf) and specifically deliver it to tumor cells to elevate the Fe2+ level. Meanwhile, the intracellular degradation product of cLAV, dihydrolipoic acid, could regenerate Fe2+ to further boost the ferroptosis. The results disclosed that T10@cLAV achieved tumor inhibition comparable to that of cisplatin at a dose as low as 5 mg/kg in the HeLa tumor-bearing nude mice model and caused no toxicity at the dose up to 300 mg/kg. This tactful iron-supplement strategy of hijacking blood Tf is superior to the current strategies: one is the induction of intracellular ferritin degradation, which is limited by the low content of ferritin, and the other is the delivery of iron-based materials, which easily causes adverse effects.


Asunto(s)
Ferroptosis , Nanopartículas , Neoplasias , Ratones , Animales , Transferrina/metabolismo , Ratones Desnudos , Hierro/metabolismo , Ferritinas , Nanopartículas/química
16.
Phytomedicine ; 128: 155539, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38522311

RESUMEN

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer (EC) in China, and demonstrates varying levels of resistance to multiple chemotherapeutic agents. Our previous studies have proved that periplocin (CPP), derived from the extract of cortex periplocae, exhibiting the capacity to hinder proliferation and induce apoptosis in ESCC cells. Several studies have identified additional anti-cancer constituents in the extract of cortex periplocae, named periplcymarin (PPM), sharing similar compound structure with CPP. Nevertheless, the inhibitory effects of PPM on ESCC and their underlying mechanisms remain to be further elucidated. PURPOSE: The aim of this study was to investigate function of PPM inhibiting the growth of ESCC in vivo and in vitro and to explore its underlying mechanism, providing the potential anti-tumor drug for ESCC. METHODS: Initially, a comparative analysis was conducted on the inhibitory activity of three naturally compounds obtained from the extract of cortex periplocae on ESCC cells. Among these compounds, PPM was chosen for subsequent investigation owing to its comparatively structure and anti-tumor activity simultaneously. Subsequently, a series of biological functional experiments were carried out to assess the impact of PPM on the proliferation, apoptosis and cell cycle arrest of ESCC cells in vitro. In order to elucidate the molecular mechanism of PPM, various methodologies were employed, including bioinformatics analyses and mechanistic experiments such as high-performance liquid chromatography combined with mass spectrometry (HPLC-MS), cell glycolysis pressure and mitochondrial pressure test. Additionally, the anti-tumor effects of PPM on ESCC cells and potential toxic side effects were evaluated in vivo using the nude mice xenograft assay. RESULTS: Our study revealed that PPM possesses the ability to impede the proliferation of ESCC cells, induce apoptosis, and arrest the cell cycle of ESCC cells in the G2/M phase in vitro. Mechanistically, PPM exerted its effects by modulating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), as confirmed by glycolysis pressure and mitochondrial pressure tests. Moreover, rescue assays demonstrated that PPM inhibits glycolysis and OXPHOS in ESCC cells through the PI3K/AKT and MAPK/ERK signaling pathways. Additionally, we substantiated that PPM effectively suppresses the growth of ESCC cells in vivo, with only modest potential toxic side effects. CONCLUSION: Our study provides novel evidence that PPM has the potential to simultaneously target glycolysis and mitochondrial OXPHOS in ESCC cells. This finding highlights the need for further investigation into PPM as a promising therapeutic agent that targets the tumor glucose metabolism pathway in ESCC.


Asunto(s)
Antineoplásicos Fitogénicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Glucólisis , Ratones Desnudos , Mitocondrias , Fosforilación Oxidativa , Saponinas , Humanos , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Línea Celular Tumoral , Fosforilación Oxidativa/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones , Proliferación Celular/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Phytomedicine ; 128: 155377, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38503154

RESUMEN

BACKGROUND: The existence of pancreatic cancer stem cells (PCSCs) results in limited survival benefits from current treatment options. There is a scarcity of effective agents for treating pancreatic cancer patients. Dehydroevodiamine (DeHE), a quinazoline alkaloid isolated from the traditional Chinese herb Evodiae fructus, exhibited potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor growth both in vitro and in vivo. METHODS: The cytotoxic effect of DeHE on PDAC cells was assessed using CCK-8 and colony formation assays. The antitumor efficacy of DeHE were appraised in human PANC-1 xenograft mouse model. Sphere formation assay and flow cytometry were employed to quantify the tumor stemness. RNA-Seq analysis, drug affinity responsive target stability assay (DARTS), and RNA interference transfection were conducted to elucidate potential signaling pathways. Western blotting and immunohistochemistry were utilized to assess protein expression levels. RESULTS: DeHE effectively inhibited PDAC cell proliferation and tumor growth in vitro and in vivo, and exhibited a better safety profile compared to the clinical drug gemcitabine (GEM). DeHE inhibited PCSCs, as evidenced by its suppression of self-renewal capabilities of PCSCs, reduced the proportion of ALDH+ cells and downregulated stemness-associated proteins (Nanog, Sox-2, and Oct-4) both in vitro and in vivo. Furthermore, there is potential involvement of DDIT3 and its downstream DDIT3/TRIB3/AKT/mTOR pathway in the suppression of stemness characteristics within DeHE-treated PDAC cells. Additionally, results from the DARTS assay indicated that DeHE interacts with DDIT3, safeguarding it against degradation mediated by pronase. Notably, the inhibitory capabilities of DeHE on PDAC cell proliferation and tumor stemness were partially restored by siDDIT3 or the AKT activator SC-79. CONCLUSION: In summary, our study has identified DeHE, a novel antitumor natural product, as an activator of DDIT3 with the ability to suppress the AKT/mTOR pathway. This pathway is intricately linked to tumor cell proliferation and stemness characteristics in PDAC. These findings suggest that DeHE holds potential as a promising candidate for the development of innovative anticancer therapeutics.


Asunto(s)
Proliferación Celular , Células Madre Neoplásicas , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Antineoplásicos Fitogénicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Evodia/química , Gemcitabina , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factor de Transcripción CHOP/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
18.
J Ethnopharmacol ; 329: 118001, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38467318

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: In 2020, liver cancer contributed to approximately 0.9 million new cases and 0.83 million deaths, making it the third leading cause of mortality worldwide. Andrographis paniculata (Burm.f.) Nees(APN), a traditional Chinese or ethnic medicine extensively utilized in Asia, has been historically employed for treating hepatitis and liver cancer. However, the precise molecular mechanism responsible for its therapeutic efficacy remains unclear. AIM OF THE STUDY: To identify and replace the active components of APN on liver cancer, which is investigate the potential of a Multi-Component Chinese Medicine derived from Andrographis paniculata (Burm.f.) Nees(APN-MCCN) for the treatment of liver cancer. MATERIALS AND METHODS: Firstly, the TCMSP database and two liver cancer disease databases were utilized to optimize the chemical constituents of APN and the disease-related targets of liver cancer. The network was constructed using Cytoscape to visualize the relationships between them. Subsequently, the optimal combination of components in APN-MCCN for the treatment of liver cancer was determined using the contribution index method. HPLC analysis was performed to measure the content of each component. Pathway enrichment and gene annotation were conducted using the ClueGo plugin. In vivo efficacy was evaluated by transplanting S180 and H22 tumor-bearing mouse models. In vitro efficacy was determined through MTT assay, morphological observations, flow cytometry analysis, and scratch tests. Western blotting was used to validate the protein expression. The transfection techniques were employed to knockdown the expressions of key protein in different pathway. RESULTS: We obtained 24 effective compounds, with andrographolide contributing 20.78%, wogonin contributing 41.85%, and oroxylin A contributing 30.26% to the overall composition. Based on the predicted enrichment degree and correlation with liver cancer, we identified a total of 27 pathways, among which the Leptin signaling pathway, AGE-RAGE signaling pathway, and Cell Cycle signaling pathway were selected for further investigation. The content of andrographolide, oroxylin A, and wogonin in APN was found to be 0.104%, 0.0024%, and 0.0052%, respectively. In vivo experiments demonstrated that APN-MCCM significantly reduced tumor weight in S180 tumor-bearing mice and prolonged the survival time of H22 liver cancer-bearing mice. APN-MCCM exhibited inhibitory effects on the proliferation, apoptosis, and migration of liver cancer cells while arresting them in the G2/M phase. Furthermore, APN-MCCM down-regulated the protein expression of NCOA1, PTPN1, and GSK3B in the Leptin signaling pathway, NOS2 and NOS3 in the AGE-RAGE signaling pathway, CCNA2, CDK1, CDK2, and CDK7 in the Cell Cycle signaling pathway. Additionally, it upregulated the protein phosphorylation of p-P38 and p-JUN in the AGE-RAGE signaling pathway. Knockout experiments revealed that the inhibitory effect of APN-MCCM on liver cancer cell migration was prevented when the MAPK or NCOA1 genes were knocked out. Similarly, knocking out the CDK7 gene blocked the G2/M phase arrest induced by APN-MCCM in liver cancer cells. CONCLUSIONS: APN-MCCM, consisting of andrographolide, wogonin, and oroxylin A, exhibits inhibitory effects on the cell proliferation of liver cancer cells by targeting the cell cycle pathway. Additionally, it suppresses the migration of liver cancer cells through the AGE-RAGE and Leptin signaling pathways.


Asunto(s)
Andrographis , Carcinoma Hepatocelular , Ciclo Celular , Proliferación Celular , Diterpenos , Flavonoides , Leptina , Neoplasias Hepáticas , Transducción de Señal , Animales , Proliferación Celular/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Diterpenos/farmacología , Diterpenos/aislamiento & purificación , Humanos , Transducción de Señal/efectos de los fármacos , Andrographis/química , Ratones , Ciclo Celular/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Leptina/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/aislamiento & purificación , Masculino , Línea Celular Tumoral , Células Hep G2 , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Flavanonas
19.
FASEB J ; 38(7): e23581, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38551642

RESUMEN

Human DEAD/H box RNA helicase DDX6 acts as an oncogene in several different types of cancer, where it participates in RNA processing. Nevertheless, the role of DDX6 in pancreatic cancer (PC), together with the underlying mechanism, has yet to be fully elucidated. In the present study, compared with adjacent tissues, the level of DDX6 was abnormally increased in human PC tissues, and this increased level of expression was associated with poor prognosis. Furthermore, the role of DDX6 in PC was investigated by overexpressing or silencing the DDX6 in the PC cell lines, SW1990 and PaTu-8988t. A xenograft model was established by injecting nude mice with either DDX6-overexpressing or DDX6-silenced SW1990 cells. DDX6 overexpression promoted the proliferation and cell cycle transition, inhibited the cell apoptosis of PC cells, and accelerated tumor formation, whereas DDX6 knockdown elicited the opposite effects. DDX6 exerted positive effects on PC. RNA immunoprecipitation assay showed that DDX6 bound to kinesin family member C1 (KIFC1) mRNA, which was further confirmed by RNA pull-down assay. These results suggested that DDX6 positively regulated the expression of KIFC1. KIFC1 overexpression enhanced the proliferative capability of PC cells with DDX6 knockdown and inhibited their apoptosis. By contrast, DDX6 overexpression reversed the inhibitory effect of KIFC1 silencing on tumor proliferation. Subsequently, the transcription factor Yin Yang 1 (YY1) was shown to negatively regulate DDX6 at both the mRNA and protein levels. Dual-luciferase reporter assay verified that YY1 targeted the promoter of DDX6 and inhibited its transcription. High expression levels of YY1 decreased the proliferation of PC cells and promoted cell apoptosis, although these effects were reversed by DDX6 overexpression. Taken together, YY1 may target the DDX6/KIFC1 axis, thereby negatively regulating its expression, leading to an inhibitory effect on pancreatic tumor.


Asunto(s)
ARN Helicasas DEAD-box , MicroARNs , Neoplasias Pancreáticas , Factor de Transcripción YY1 , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , MicroARNs/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismo
20.
Mol Pain ; 20: 17448069241240692, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38443317

RESUMEN

Pain is a major symptom in cancer patients, and cancer-induced bone pain (CIBP) is the most common type of moderate and severe cancer-related pain. The current available analgesic treatments for CIBP have adverse effects as well as limited therapeutic effects. Acupuncture is proved effective in pain management as a safe alternative therapy. We evaluated the analgesic effect of acupuncture in treatment of cancer pain and try to explore the underlying analgesic mechanisms. Nude mice were inoculated with cancer cells into the left distal femur to establish cancer pain model. Electroacupuncture (EA) treatment was applied for the xenograft animals. Pain behaviors of mice were evaluated, followed by the detections of neuropeptide-related and inflammation-related indicators in peripheral and central levels. EA treatment alleviated cancer-induced pain behaviors covering mechanical allodynia, thermal hyperalgesia and spontaneous pain, and also down-regulated immunofluorescence expressions of neuropeptide CGRP and p75 in the skin of affected plantar area in xenograft mice, and inhibited expressions of overexpressed neuropeptide-related and inflammation-related protein in the lumbar spinal cord of xenograft mice. Overall, our findings suggest that EA treatment ameliorated cancer-induced pain behaviors in the mouse xenograft model of cancer pain, possibly through inhibiting the expressions of neuropeptide-related and inflammation-related protein in central level following tumor cell xenografts.


Asunto(s)
Dolor en Cáncer , Electroacupuntura , Neoplasias , Neuropéptidos , Ratas , Humanos , Ratones , Animales , Dolor en Cáncer/etiología , Dolor en Cáncer/terapia , Dolor en Cáncer/metabolismo , Nocicepción , Ratones Desnudos , Ratas Sprague-Dawley , Dolor/metabolismo , Hiperalgesia/complicaciones , Hiperalgesia/terapia , Hiperalgesia/inducido químicamente , Analgésicos/metabolismo , Inflamación/metabolismo , Médula Espinal/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA