RESUMO
Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.
Assuntos
Chalconas , Melanoma , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Melanoma/metabolismo , Diferenciação Celular , Via de Sinalização Wnt , Serina-Treonina Quinases TOR/metabolismo , Proliferação de Células , Movimento Celular , Linhagem Celular TumoralRESUMO
Studies on clear cell renal cell carcinoma (ccRCC) are gaining momentum due to its high malignancy and potential to metastasize. Fbox protein 30 (FBXO30) is a member of the Fbox protein family; however, its role and mechanism in cancer remains to be fully elucidated. Western blotting, reverse transcriptionquantitative PCR and immunohistochemsitry were performed to detect the expression levels of FBXO30 in ccRCC tissues and adjacent normal tissues. Tumor biological function assays and animal experiments were conducted to clarify the inhibitory effect of FBXO30 on the progression and metastasis of ccRCC. Protein halflife assay, MG132 inhibition assay, immunofluorescence assay and coimmunoprecipitation assay were performed to explore the ubiquitination mechanism of FBXO30 and HIF1α. Zinc supplementation assay was used to verify the regulatory relationship between human ZRT, IRTlike protein 1 (hZIP1), FBXO30 and HIF1α. The present study revealed that the expression levels of FBXO30 were lower in ccRCC tissues compared with those in normal adjacent tissues. In addition, FBXO30 inhibited the tumorigenesis and metastatic capacity of ccRCC cells in vivo and in vitro. FBXO30 mediated the ubiquitination and degradation of hypoxiainducible factor1α (HIF1α) in ccRCC cells under normoxia, thereby inhibiting the oncogenic effect of HIF1α. Notably, hZIP1 served as an upstream regulator of FBXO30, regulating the expression of FBXO30 and HIF1α by recruiting Zn2+. In conclusion, the present data suggested that FBXO30 is a novel E3 ubiquitination ligase that can function as a tumor suppressor in ccRCC, and the hZIP1/Zn2+/FBXO30/HIF1α axis may provide potential biomarkers or therapeutic targets for ccRCC.
Assuntos
Carcinoma de Células Renais , Proteínas F-Box , Neoplasias Renais , Animais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas F-Box/genética , Proteínas F-Box/metabolismoRESUMO
Cisplatin is one of the principal platinum-based chemotherapeutic agents for many types of cancer, including non-small-cell lung cancer (NSCLC). Copper transporter 1 (CTR1) plays a significant role in increasing cellular cisplatin uptake and sensitivity. The current study found that glucose restriction upregulated AMPK (AMP-activated protein kinase) through reactive oxygen species (ROS) to induce CTR1 expression in NSCLC cells. Direct upregulation of ROS levels also activated AMPK expression. The changes in CTR1 expression were consistent with glucose concentrations and AMPK expression. Feeding a low-carbohydrate ketogenic diet (a glucose restriction diet) to a severe combined immune deficiency (SCID) mouse xenograft model significantly enhanced the efficacy of cisplatin. The tumor size was significantly smaller in the group treated with cisplatin plus the low-carbohydrate ketogenic diet than in the group treated with cisplatin alone. Survival was longer in mice treated with the low-carbohydrate ketogenic diet than in the controls. Mice fed the low-carbohydrate ketogenic diet showed increased expression of CTR1 and AMPK in tumor tissues. These results suggest a novel mechanism whereby glucose restriction induces ROS-AMPK-mediated CTR1 expression in NSCLC, indicating glucose restriction as an effective adjuvant NSCLC therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Proteínas de Transporte de Cátions , Neoplasias Pulmonares , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/uso terapêutico , Cisplatino , Transportador de Cobre 1 , Glucose , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Ginkgo biloba L. has been used in traditional Chinese medicine (TCM) for thousands of years. However, the anti-cancer properties of ginkgolic acids (GAS) isolated from G. biloba have not been investigated in human nasopharyngeal carcinoma cells. In this study, GAS exhibited an inhibitory effect on the ATPase activity of heat shock protein 90 (Hsp90) and anti-proliferative activities against four human cancer cell lines, with IC50 values ranging from 14.91 to 23.81 µg·mL-1. In vivo experiments confirmed that GAS inhibited tumor growth in CNE-2Z cell-xenografted nude mice with low hepatotoxicity. We further demonstrated that GAS suppressed migration and invasion and induced the apoptosis of CNE-2Z cells by inducing the degradation of Hsp90 client proteins (MMP-2, MMP-9, Her-2, c-Raf, Akt, and Bcl-2). Together, GAS are new Hsp90 inhibitors by binding to Hsp90 (hydrogen bond and hydrophobic interaction). Thus, GAS from G. biloba might represent promising Hsp90 inhibitors for the development of anti-nasopharyngeal carcinoma agents.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ginkgo biloba/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Salicilatos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Salicilatos/química , Salicilatos/isolamento & purificação , Células Tumorais CultivadasRESUMO
Non-small cell lung cancer (NSCLC) constitutes nearly 85% of all cases of lung cancer. Drug resistance, dose-limiting toxicity, and metastasis in NSCLC eventually reduce the efficacy of chemotherapeutics. In this study, we have shown that the methanol-ethyl acetate partitioned fraction from Magnolia grandiflora L. seeds (MEM) exhibit potential anti-cancer activities against NSCLC H1975 cells in vivo and in vitro. MEM significantly inhibited the proliferation of H1975 cells in a concentration- and time-dependent manner. Further, MEM exhibited potent anti-tumor efficacy and low toxicity in nude mice bearing H1975 tumors. Our study also showed that MEM could induce cellular apoptosis in H1975 cells by down-regulating the protein expression levels of Akt and p-Akt-473, and by increasing the ratio of Bax/Bcl-2. Also, MEM significantly inhibited metastasis-related cell invasion and migration of H1975 cells, which associated with the down-regulation of HIF-1α, MMP-2, and MMP-9 protein expression levels. Thus, our data shows that MEM may be an effective fraction of M. grandiflora in NSCLC treatment.
Assuntos
Acetatos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Magnolia/química , Metanol/uso terapêutico , Animais , Humanos , Camundongos , Camundongos NusRESUMO
OBJECTIVE: To investigate the effects of methanol-ethyl acetate partitioned fractions from Descurainia sophia (MEDS) on the proliferation and apoptosis of human non-small cell lung cancer H1975 cells. METHODS: The systemic solvent extraction method was used to preliminary separation of the effective fractions in the methanol extract of Descurainia sophia. The cytotoxicity of each extract (5, 10, 20, 40, and 80 µg/mL) was tested using MTT assay. Colony cloning method was used to assess the effect of different concentrations of methanol-ethyl acetate partitioned fractions from MEDS (5, 10, 20, 40, and 80 µg/ mL) on the proliferation of H1975 cells. Flow cytometric analysis with Annexin V-FITC/PI staining was performed to detect the apoptosis of the cells after treatment with different concentrations of MEDS fractions (10, 20, and 40 µg/mL). Western blotting was used to evaluate the effects of MEDS fractions on the expressions of apoptosis-related proteins Akt, Bax, and Bcl-2. The anti-tumor activity of 100 mg/kg MEDS fractions was tested in a nude mouse model bearing H1975 cell xenografts. RESULTS: MTT assay and colony forming experiment showed that MEDS fractions significantly inhibited the proliferation of H1975 cells in a dose-and time-dependent manner (P < 0.05). The results of flow cytometry showed that MEDS fractions induced obvious apoptosis of H1975 cells in a concentration-dependent manner (P < 0.05). MEDS fractions also significantly decreased the expressions of Bcl-2 and Akt protein and increased the protein expression of Bax (P < 0.05). In the tumor-bearing nude mouse model, MEDS fractions showed potent anti-tumor effects with a low toxicity to affect the body weight and organs of the mice. CONCLUSIONS: The methanol-ethyl acetate partitioned fractions from MEDS show potent anti-tumor activity both in vivo and in vitro, suggesting their value as promising therapeutic agents against lung cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Extratos Vegetais/farmacologia , Acetatos , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Metanol , Camundongos , Camundongos Nus , Extratos Vegetais/isolamento & purificaçãoRESUMO
GOAL: The construction of single-cell array is known as the challenging technology to manipulate cell position and number and accomplish cell analysis in biomedical engineering. METHODS: We put forward a novel controllable cell printing technique for rapid, precise, convenient, high cell viability, multicellular, and high-throughput printing. We also proposed a novel microfluidic device to verify the effectiveness of the printing and study the migration ability and anti-cancer drug responses of cancer cell as important applications. RESULTS: This technique offered a minimum process time of 5 min, a maximum positional accuracy of 10 µm, 0.1 nL liquid volume level per droplet, above 87% cell viability after seven days and the ability to print different multicellular arrays. We found that the cell compared to cell culture in petri dish after 48 h. In addition, there was a significant different inhibition on cancer cells migration ability and cell drug activities with different concentrations of paclitaxel. CONCLUSION: This novel controllable cell array printing technique on the microfluidic platforms provides a useful method with high-quality printing and cell viability for the applications of single-cell analysis and high-throughput drug screening. SIGNIFICANCE: The controllable cell printing technique could apply in many biological processes and biomedical engineering applications, such as cell analysis, cancer development, and drug screening and metabolism. Combined with the microfluidic chips, tissue engineering, and sensors, this technique will be widely used for the construction and analysis of biological and biomedical model.