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Lung cancer (LC) is the leading cause of cancer deaths worldwide. Surgery, chemoradiotherapy, targeted therapy, and immunotherapy are considered dominant treatment strategies for LC in the clinic. However, drug resistance and meta-stasis are two major challenges in cancer therapies. Medicarpin (MED) is an isoflavone compound isolated from alfalfa, which is usually used in traditional medicine. This study was de sig ned to evaluate the anti-LC effect and reveal the underlying mechanisms of MED in vivo and in vitro. We found that MED could significantly inhibit proliferation, induce apoptosis, and cell cycle arrest of A549 and H157 cell lines. Basically, MED induced cell apoptosis of LC cells by upregu lating the expression of pro-apoptotic proteins BAX and Bak1, leading to the cleavage of caspase-3 (Casp3). Moreover, MED inhibited the proliferation of LC cells via downregulating the expression of proliferative protein Bid. Overall, MED inhibited LC cell growth in vitro and in vivo via suppressing cell proliferation and inducing cell apoptosis, suggesting the therapeutic potential of MED in treating LC.
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Neoplasias Pulmonares , Pterocarpanos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Línea Celular Tumoral , Apoptosis , Fitoalexinas , Proliferación CelularRESUMEN
BACKGROUND: The mortality rate of liver cancer ranks third in the world, and hepatocellular carcinoma (HCC) is a malignant tumor of the digestive tract. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae spp., is the main active component of Chinese patent medicine the Cucurbitacin Tablet, which has been widely used in the treatment of various malignant tumors in clinics, especially HCC. PURPOSE: This study explored the role and mechanism of CuB in the suppression of liver cancer progression. METHODS: Cell Counting Kit-8 (CCK-8) and colony formation assays were used to detect the inhibitory function of CuB in Huh7, Hep3B, and Hepa1/6 hepatoma cells. Calcein-AM/propidium iodide (PI) staining and lactate dehydrogenase (LDH) measurement assays were performed to determine cell death. Mitochondrial membrane potential (Δψm) was measured, and flow cytometry was performed to evaluate cell apoptosis and cell cycle. Several techniques, such as proteomics, Western blotting (WB), and ribonucleic acid (RNA) interference, were utilized to explore the potential mechanism. The animal experiment was performed to verify the results of in vitro experiments. RESULTS: CuB significantly inhibited the growth of Huh7, Hep3B, and Hepa1/6 cells and triggered the cell cycle arrest in G2/M phage without leading to cell death, especially apoptosis. Knockdown of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a target of CuB, did not reverse CuB elicited cell cycle arrest. CuB enhanced phosphorylated ataxia telangiectasia mutated (p-ATM) and phosphorylated H2A histone family member X (γ-H2AX) levels. Moreover, CuB increased p53 and p21 levels and decreased cyclin-dependent kinase 1 (CDK1) expression, accompanied by improving phosphorylated checkpoint kinase 1 (p-CHK1) level and suppressing cell division cycle 25C (CDC25C) protein level. Interestingly, these phenomena were partly abolished by a deoxyribonucleic acid (DNA) protector methylproamine (MPA). Animal studies showed that CuB also significantly suppressed tumor growth in BALB/c mice bearing Hepa1/6 cells. In tumor tissues, CuB reduced the expression levels of proliferating cell nuclear antigen (PCNA) and γ-H2AX but did not change the terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) level. CONCLUSION: This study demonstrated for the first time that CuB could effectively impede HCC progression by inducing DNA damage-dependent cell cycle arrest without directly triggering cell death, such as necrosis and apoptosis. The effect was achieved through ataxia telangiectasia mutated (ATM)-dependent p53-p21-CDK1 and checkpoint kinase 1 (CHK1)-CDC25C signaling pathways. These findings indicate that CuB may be used as an anti-HCC drug, when the current findings are confirmed by independent studies and after many more clinical phase 1, 2, 3, and 4 testings have been done.
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Ataxia Telangiectasia , Carcinoma Hepatocelular , Neoplasias Hepáticas , Triterpenos , Animales , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/uso terapéutico , Puntos de Control del Ciclo Celular , Daño del ADN , Apoptosis , Línea Celular Tumoral , Proliferación CelularRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Laetiporus sulphureus has long been used as an edible and medicinal mushroom in Asia, America, and Europe. Its fruiting bodies are widely used in folk medicine for treating cancer, gastric diseases, cough, and rheumatism. Polysaccharides are an important bioactive component of mushrooms. In nature, sulfated polysaccharides have never been reported in mushrooms. Furthermore, there is no information on differences in physicochemical properties and anti-breast cancer activities between polysaccharides (PS) and sulfated polysaccharides (SPS) of L. sulphureus. AIM OF THE STUDY: This study aimed to investigate the physicochemical properties of PS and SPS isolated from fruiting bodies of L. sulphureus and examine their anti-proliferative effects and mechanism(s) of action on MDA-MB-231 breast cancer cells. METHODS: Polysaccharides (PS) were isolated using hot water and ethanol precipitation methods. Sulfated polysaccharides (SPS) were isolated by the papain-assisted hydrolysis method. Physicochemical properties comprising sugar, protein, uronic acid, and sulfate contents, and molecular weight, monosaccharide composition, and structural conformation were analyzed on PS and SPS. In the anti-cancer study, a triple-negative breast cancer cell line (MDA-MB-231) and a normal human mammary epithelial cell line (H184B5F5/M10) were used to evaluate the anti-proliferative activity of PS and SPS, and their mechanism(s) of action. RESULTS: The results showed that SPS, which had higher sulfate and protein contents and diversified monosaccharide composition, exhibited more potent anti-proliferative activity against MDA-MB-231 cells than PS. Furthermore, it had a selective cytotoxic effect on breast cancer cells but not the normal cells. SPS induced cell cycle arrest at G0/G1 phase via down-regulating CDK4 and cyclin D1 and up-regulating p21 protein expression. Breast cancer cell apoptosis was not observed until 72 h after SPS treatment. In addition, SPS also markedly inhibited breast cancer cell migration. CONCLUSION: This study demonstrates that SPS exhibited selective cytotoxicity and was more potent than PS in inhibiting MDA-MB-231 cell proliferation. The contents of sulfate and protein, and monosaccharide composition could be the main factors affecting the anti-breast cancer activity of L. sulphureus SPS.
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Agaricales , Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Sulfatos/análisis , Puntos de Control del Ciclo Celular , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Polisacáridos/análisis , Apoptosis , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Cuerpos Fructíferos de los Hongos/química , Movimiento Celular , Monosacáridos/análisis , Línea Celular Tumoral , Ciclo CelularRESUMEN
BACKGROUND AND PURPOSE: Epiberberine (EPI) is one of the most important bioalkaloid found in the rhizome of Coptis chinensis, which has been observed to exhibit pharmaceutical effects against gastric cancer (GC). Nevertheless, the potential mechanism of EPI against GC cells still remains unclear. This study aimed to identify the core receptor on GC cells through which EPI inhibited the growth of GC cells and to explore the underlying inhibitory mechanisms. METHODS: To identify hub receptor targets that respond to EPI treatment, RNA sequencing (RNA-Seq) data from a tumor-bearing mouse model were analyzed using bioinformatics method and molecular docking. The binding interaction between EPI and GABRB3 was validated through western blotting based-cellular thermal shift assay (WB-CETSA). To further verify the binding region between EPI and GABRB3 through circular dichroism (CD) chromatography, fragments of the extracellular and transmembrane domains of the GABRB3 protein were expressed and purified in vitro. Stable cell lines with the overexpression or knockdown of GABRB3 were established using the recombinant lentivirus system. MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)) assay, colony formation assay, invasion and migration experiments, and flow cytometry were conducted to validate the inhibitory effect of EPI on the GC cells via GABRB3. Additionally, western blotting was utilized to explore the potential inhibitory mechanisms. RESULTS: Through the combination of multiple bioinformatics methods and molecular docking, we found that the γ-aminobutyric acid type A receptor subunit -ß3 (GABRB3) might be the critical receptor target in response to EPI treatment. The results of WB-CETSA analysis indicated that EPI significantly promoted the thermostability of the GABRB3 protein. Importantly, EPI could directly bind to GABRB3 and alter the secondary structure of GABRB3 fragments similar to the natural agonist, γ-aminobutyric acid (GABA). The EPI-induced suppression of the malignant phenotype of GC cells was dependent on the presence of GABRB3. GABRB3 expression was positively correlated with TP53 in patients with GC. The binding of EPI to GABRB3 stimulated p53 accumulation in GC cells. This activated the p21/CDK1/cyclinB1 pathway, resulting in G2/M cell cycle arrest, and induced the Bcl-2/BAX/Caspase axis-dependent cell apoptosis. CONCLUSION: This study revealed the target receptor for EPI in GC cells and provided new insights into its anticancer mechanisms.
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Berberina/análogos & derivados , Neoplasias Gástricas , Humanos , Ratones , Animales , Neoplasias Gástricas/genética , Proliferación Celular , Línea Celular Tumoral , Receptores de GABA/metabolismo , Proteína p53 Supresora de Tumor , Simulación del Acoplamiento Molecular , Puntos de Control de la Fase G2 del Ciclo Celular , ApoptosisRESUMEN
BACKGROUND: In the present study, Selenium Nanoparticles (SeNPs) were prepared using Bacillus coagulans, which is a type of Lactic Acid Bacteria (LAB), and then they were applied to treat breast cancer cells. METHODS: The chemicophysical properties of the bioengineered SeNPs were investigated by Transmission Electron Microscopy (TEM), Field Emission Scanning Electron Microscopy (FE-SEM), zeta potential, dynamic light scattering, Fourier Transform Infrared Spectroscopy (FT-IR), energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction analysis (XRD). The cytotoxic potential of SeNPs was evaluated by MTT assay against MCF-7 breast cancer cell line. The expression levels of apoptotic genes including BAX, BCL2, VEGF, ERBB2, CASP3, CASP9, CCNE1, CCND1, MMP2 and MMP9 were determined by real-time PCR. The rate of apoptosis and necrosis of the cancer cells as well as the results of the cell cycle were evaluated by flow cytometry method. RESULTS: The synthesized SeNPs had an average particle size of about 24-40 nm and a zeta potential of -16.1 mV, indicating the high stability of SeNPs. EDX results showed presence of SeNPs because amount of selenium in SeNPs was 86.6 % by weight. The cytotoxicity results showed a concentration-dependent effect against MCF-7 cells. The half-maximal inhibitory concentration (IC50) values of B. coagulans supernatant and SeNPs against breast cancer cells were 389.7 µg/mL and 17.56 µg/mL, respectively. In addition, SeNPs synthesized by the green process exhibited enhanced apoptotic potential in MCF-7 cancer cells compared with bacterial supernatants. Cancer cells treated with IC50 concentration of SeNPs induced 32 % apoptosis compared to untreated cells (3 % apoptosis). The gene expression levels of BAX, CASP3, and CASP9 were upregulated, while the expression levels of BCL2, CCNE1, CCND1, MMP2, MMP9, VEGF, and ERBB2 were downregulated after SeNPs treatment of cells. The potential of SeNPs to induce cell apoptosis was demonstrated by the increase in the expression level of BAX gene and the decrease in the expression level of BCL2 after treatment of cancer cells with SeNPs. CONCLUSION: The obtained results indicated that SeNPs had strong potential to induce significant cell apoptosis and are cytotoxic against the MCF-7 cancer cell line.
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Antineoplásicos , Bacillus coagulans , Neoplasias de la Mama , Nanopartículas , Selenio , Humanos , Femenino , Selenio/farmacología , Selenio/química , Caspasa 3 , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz , Espectroscopía Infrarroja por Transformada de Fourier , Factor A de Crecimiento Endotelial Vascular , Proteína X Asociada a bcl-2 , Nanopartículas/química , Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Phenolic compounds present in plants have demonstrated several biological properties such as antioxidant, antitumor, cardioprotective, and antiproliferative. On the other hand, doxorubicin, a chemotherapeutic widely used to treat breast cancer, usually exhibits chronic cardiotoxicity associated with oxidative stress. Therefore, we aimed to study the effects of phenolic compound-enriched extract (PCEE) with doxorubicin in breast cancer. To achieve this, after an SPE-C18 -column purification process of crude extracts obtained from pecan nutshells (Carya illinoinensis), the resulting PCEE was used to evaluate the cytotoxicity and antioxidant properties against the human breast cancer cell line MDA-MB-231 and the normal-hamster ovary cell line CHO-K1. PCEE was selectively cytotoxic against both cell lines, with an IC50 value (≈26.34 mg/L) for MDA-MB-231 lower than that obtained for CHO-K1 (≈55.63 mg/L). As a cytotoxic mechanism, PCEE inhibited cell growth by G2/M cell cycle arrest in MDA-MB-231 cells. Simultaneously, the study of the antioxidant activity showed that PCEE had a cytoprotective effect, evidenced by reduced ROS production in cells with oxidative stress caused by doxorubicin. The results highlight PCEE as a potential antitumor agent, thus revaluing it as an agro-industrial residue.
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Antineoplásicos , Neoplasias de la Mama , Carya , Humanos , Femenino , Polifenoles/farmacología , Polifenoles/uso terapéutico , Neoplasias de la Mama/patología , Antioxidantes/farmacología , Antioxidantes/química , Células MDA-MB-231 , Línea Celular Tumoral , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antineoplásicos/farmacología , Proliferación Celular , Fenoles/farmacología , Doxorrubicina/farmacología , ApoptosisRESUMEN
Flavopiridol is a flavone synthesized from the natural product rohitukine, which is derived from an Indian medicinal plant, namely Dysoxylum binectariferum Hiern. A deeper understanding of the biological mechanisms by which such molecules act may allow scientists to develop effective therapeutic strategies against a variety of life-threatening diseases, such as cancer, viruses, fungal infections, parasites, and neurodegenerative diseases. Mechanistic insight of flavopiridol reveals its potential for kinase inhibitory activity of CDKs (cyclin-dependent kinases) and other kinases, leading to the inhibition of various processes, including cell cycle progression, apoptosis, tumor proliferation, angiogenesis, tumor metastasis, and the inflammation process. The synthetic derivatives of flavopiridol have overcome a few demerits of its parent compound. Moreover, these derivatives have much improved CDK-inhibitory activity and therapeutic abilities for treating severe human diseases. It appears that flavopiridol has potential as a candidate for the formulation of an integrated strategy to combat and alleviate human diseases. This review article aims to unravel the potential therapeutic effectiveness of flavopiridol and its possible mechanism of action.
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Antineoplásicos , Neoplasias , Humanos , Flavonoides/farmacología , Flavonoides/uso terapéutico , Quinasas Ciclina-Dependientes , Fosforilación , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , ApoptosisRESUMEN
BACKGROUND: Resilience is the capacity for physical and emotional recovery from stressful events like cancer diagnosis and treatment. OBJECTIVES: The objectives of this study were to review existing literature to understand and illustrate ways to assess and manage resilience when providing holistic care to older adults with cancer. METHODS: A review of the literature was conducted with a focus on assessment, management, and preservation of resilience in older adults with cancer. FINDINGS: Interventions to support resilience include managing problems that occur in the areas of nutrition, exercise, social support, cognition, functional status, and emotion. Cell cycle arrest using pharmacologic agents may provide a novel proactive approach to protect resilience from deteriorating during chemotherapy to treat cancer. The oncology nurse can assess and manage resilience. which can lead to better treatment outcomes.
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Neoplasias , Enfermeras Clínicas , Humanos , Anciano , Neoplasias/tratamiento farmacológico , Cognición , Ejercicio Físico , Estado NutricionalRESUMEN
Prostate cancer (PC) is the second leading cause of cancer-related death among men. Treatment of PC becomes difficult after progression because PC that used to be androgen-dependent becomes androgen-independent prostate cancer (AIPC). Veratramine, an alkaloid extracted from the root of the Veratrum genus, has recently been reported to have anticancer effects that work against various cancers; however, its anticancer effects and the underlying mechanism of action in PC remain unknown. We investigated the anticancer effects of veratramine on AIPC using PC3 and DU145 cell lines, as well as a xenograft mouse model. The antitumor effects of veratramine were evaluated using the CCK-8, anchorage-independent colony formation, trans-well, wound healing assays, and flow cytometry in AIPC cell lines. Microarray and proteomics analyses were performed to investigate the differentially expressed genes and proteins induced by veratramine in AIPC cells. A xenograft mouse model was used to confirm the therapeutic response and in vivo efficacy of veratramine. Veratramine dose dependently reduced the proliferation of cancer cells both in vitro and in vivo. Moreover, veratramine treatment effectively suppressed the migration and invasion of PC cells. The immunoblot analysis revealed that veratramine significantly downregulated Cdk4/6 and cyclin D1 via the ATM/ATR and Akt pathways, both of which induce a DNA damage response that eventually leads to G1 phase arrest. In this study, we discovered that veratramine exerted antitumor effects on AIPC cells. We demonstrated that veratramine significantly inhibited the proliferation of cancer cells via G0/G1 phase arrest induced by the ATM/ATR and Akt pathways. These results suggest that veratramine is a promising natural therapeutic agent for AIPC.
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Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Animales , Ratones , Andrógenos/farmacología , Andrógenos/uso terapéutico , Proliferación Celular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Ciclo Celular , Línea Celular Tumoral , Apoptosis , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/farmacologíaRESUMEN
Cancer is a disease with the highest mortality and morbidity rate worldwide. First-line drugs induce several side effects that drastically reduce the quality of life of people with this disease. Finding molecules to prevent it or generate less aggressiveness or no side effects is significant to counteract this problem. Therefore, this work searched for bioactive compounds of marine macroalgae as an alternative treatment. An 80% ethanol extract of dried Caulerpa sertularioides (CSE) was analyzed by HPLS-MS to identify the chemical components. CSE was utilized through a comparative 2D versus 3D culture model. Cisplatin (Cis) was used as a standard drug. The effects on cell viability, apoptosis, cell cycle, and tumor invasion were evaluated. The IC50 of CSE for the 2D model was 80.28 µg/mL versus 530 µg/mL for the 3D model after 24 h of treatment exposure. These results confirmed that the 3D model is more resistant to treatments and complex than the 2D model. CSE generated a loss of mitochondrial membrane potential, induced apoptosis by extrinsic and intrinsic pathways, upregulated caspases-3 and -7, and significantly decreased tumor invasion of a 3D SKLU-1 lung adenocarcinoma cell line. CSE generates biochemical and morphological changes in the plasma membrane and causes cell cycle arrest at the S and G2/M phases. These findings conclude that C. sertularioides is a potential candidate for alternative treatment against lung cancer. This work reinforced the use of complex models for drug screening and suggested using CSE's primary component, caulerpin, to determine its effect and mechanism of action on SKLU-1 in the future. A multi-approach with molecular and histological analysis and combination with first-line drugs must be included.
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Caulerpa , Neoplasias Pulmonares , Humanos , Caulerpa/química , Calidad de Vida , Extractos Vegetales/farmacología , Extractos Vegetales/química , Puntos de Control del Ciclo Celular , Neoplasias Pulmonares/metabolismo , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Proliferación CelularRESUMEN
One of the most common cancers that result in death is lung cancer. There is new hope in the fight against lung cancer thanks to the chemopreventive properties of natural dietary substances like ß-caryophyllene oxide (CPO), and research is currently being done to test this theory. CPO, a sesquiterpene isolated from medicinal plant essential oils, inhibits carcinogenesis and has been effective in treating many cancers. This study examined how CPO affected proliferation of human lung cancer A549 cells. CPO was found to have an inhibitory concentration (IC50) of 124.1 g/ml. The proliferative markers Ki67 and PCNA were significantly inhibited after cells were treated with CPO at a concentration of 50 g/ml compared to controls. CPO-treated cells expressed more P21, P53, and DNA strand breaks than controls. This was accompanied by a significant cell cycle arrest in the S and G2/M phases. In treated A549 cells, this was also associated with a significant induction of apoptosis, as shown by the upregulation of the expression of caspases 3, 7, and 9, as well as Bax, and the downregulation of Bcl-2. Furthermore, the redox status of treated A549 cells revealed a marked rise in GSH and GPx activity levels and a decline in 4-HNE levels, indicating low oxidative stress following CPO treatment of A549 cells. In conclusion, cell cycle arrest and apoptosis, which are unrelated to oxidative stress, were the mechanisms by which CPO reduced cancer lung cell growth. This finding might be a potential therapeutic target for the treatment of lung cancer. Hypothetical scheme of CPO anticancer effects (mechanism of signaling) in A549 cells; in vitro. CPO treatment increases expression of p21, p53 and DNA fragmentation. These events cause arrest of cell cycle which was associated with significant induction in apoptosis via increase expression of caspases (-3,-7,-9), and Bax and downregulation of Bcl-2.
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Neoplasias Pulmonares , Proteína p53 Supresora de Tumor , Humanos , Células A549 , Proteína X Asociada a bcl-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , División Celular , Caspasas/metabolismo , Caspasas/farmacología , Caspasas/uso terapéutico , Proliferación CelularRESUMEN
Traditionally, the bark of Uncaria rhynchophylla (UR) has been employed for the treatment of hypertension, cancer, convulsions, haemorrhage, autoimmune disorders and other ailments. The primary aim of the present study was to explore the antiproliferative activity of hirsuteine (HTE) isolated from UR over a range of concentrations in human NSCLC NCI-H1299 cells and to explore the mechanisms underlying its therapeutic efficacy. The effects of HTE on cell viability were examined using Cell Counting Kit-8 (CCK-8) and colony formation assays, while apoptosis was assessed by flow cytometry. Cell cycle progression was additionally evaluated via propidium iodide staining, while reverse transcription-quantitative PCR and western blotting methods were employed to assess the protein levels and genes related to apoptosis and progression of the cell cycle, respectively. NCI-H1299 cell proliferation was markedly suppressed by HTE in a time- and dose-dependent manner. However, clear changes in cell morphology were also induced, resulting in G0-G1 phase cell cycle arrest, which was associated with cyclin E and CDK2 downregulation. HTE additionally induced robust NSCLC NCI-H1299 cell apoptosis, downregulation of Bcl-2 and upregulation of cytoplasmic cytochrome C, Bax, Apaf1, cleaved caspase-3 and cleaved caspase-9, which together drove the observed apoptotic cell death. HTE could effectively suppress human NSCLC NCI-H1299 cell growth by inducing apoptotic death in a dose-dependent fashion in vitro, therefore elucidating the mechanism by which this phytomedicine acts as a potent anticancer compound that warrants study as a treatment for human NSCLC patients.
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Introduction: After surgery, radiotherapy is the most common technique to treat breast cancer. Over the past decades, the thermal effects of radiofrequency-wave hyperthermia combined with radiotherapy have been used to increase radiosensitivity in cancer treatment. The cells have various radiation and thermal sensitivities at different stages of the mitotic cycle. Furthermore, ionizing radiation and the thermal effect of hyperthermia affect the cells' mitotic cycle and can partly induce cell cycle arrest. However, the time interval between hyperthermia and radiotherapy, as an essential factor influencing hyperthermia effect on cancer cells' cycle arrest, has not been studied before. In this study, we investigated the effect of hyperthermia on the MCF7 cancer cell cycle arrest in mitotic cycles at various selected time intervals after hyperthermia to find and propose appropriate time intervals between hyperthermia and radiotherapy. Method and Materials: In this experimental study, we used the MCF7 breast cancer cell line to investigate the effect of 13.56 MHz hyperthermia (at a temperature of 43°C for a period of 20 min) on their cell cycle arrest. We performed the flowcytometry assay to assess the changes in the mitotic phases of the cell population at different time intervals (1, 6, 24, and 48 h) after hyperthermia. Results: Our flowcytometry results indicated the 24-h time interval has the most significant effect on the cell population at S and G2/M phases. Therefore, the 24-h time interval can be proposed as the most appropriate time after hyperthermia for carrying out combinational radiotherapy procedure. Conclusion: Among various investigated time intervals examined in our research, the 24-h time interval can be proposed as the most appropriate time between hyperthermia and radiotherapy for combinational therapy of breast cancer cells.
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Neoplasias de la Mama , Hipertermia Inducida , Humanos , Femenino , Neoplasias de la Mama/radioterapia , Puntos de Control del Ciclo Celular , Células MCF-7 , División Celular , Ciclo CelularRESUMEN
BACKGROUND: Acquired resistance to doxorubicin (DOX) inevitably limits its clinical use against breast cancer (BC). Isorhamnetin (IS), a native flavonoid which extensively available in vegetables, fruits, and phytomedicine, has been deemed to the probable cancer chemopreventive agent in preceding explorations since it exhibits satisfied antitumor activity. So far, the strategy for alleviating DOX resistance by using IS as a sensitizer against resistant BC has not yet been covered. PURPOSE: To investigate the effect of IS on potentiating the chemoreceptivity of drug-resistant BC cells to DOX in vitro and in vivo and elucidate the possible molecular mechanisms. METHODS: MTS assays, colony formation assays, three-dimensional (3D) tumor spheroid model, and migration assay were deployed to verify the inhibiting action of IS in the presence or absence of DOX on resistant BC cells in vitro. Apoptosis, cell cycle regulation, and endocellular reactive oxygen species (ROS) were determined by flow cytometry. Protein levels were monitored by western blotting. Nuclear staining and EdU proliferation were photographed with a confocal laser scanning microscope. The effects of the IS and DOX combination on the tumorigenesis in the xenograft experiments were evaluated for further confirming the in vitro cytotoxicity. RESULTS: IS significantly inhibited cell proliferation and migration and enhanced the antitumor competence of DOX against resistant BC cells both in vitro and in vivo. Adjuvant IS (50 µM) effectively enhanced the proapoptotic impacts of DOX in resistant BC cells (35.38 ± 3.18%, vs. 5.83 ± 0.68% in the DOX group) by suppressing the expression of bcl 2 in addition to enhancing cleaved caspase 3, ultimately leading to DNA condensation and fragmentation. IS (20, 30, and 50 µM) treatments induced significant increases in the G2/M populations (41.60 ± 1.28%, 44.60 ± 1.14%, and 50.64 ± 0.67%, vs. 35.84 ± 1.56% in the untreated control in MCF7/ADR cells, p < 0.01) via regulating CDK1/Cyclin B1 complex expression, subsequently triggering the inhibition of BC proliferation. In addition, IS (10, 20, 30, and 50 µM) stimulated the production of interstitial ROS in MCF7/ADR cells, by 3.99-, 4.20-, 6.29-, and 6.78-fold, respectively, versus the untreated group (p < 0.001), which were involved in DNA damage and AMPK-caused intercept of the mTOR/p70S6K signaling. CONCLUSION: Our study suggested the anti-breast cancer actions of IS as a DOX sensitizer and expounded the underlying molecular mechanisms, showing that IS could be deemed to a capable alternative for resistant BC cure.
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Proteínas Quinasas Activadas por AMP , Neoplasias de la Mama , Humanos , Femenino , Proteínas Quinasas Activadas por AMP/metabolismo , Especies Reactivas de Oxígeno , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Doxorrubicina/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Transducción de Señal , Apoptosis , Proliferación Celular , Serina-Treonina Quinasas TOR/metabolismo , Daño del ADNRESUMEN
Caralluma europaea is a medicinal plant used in Moroccan popular medicine, which has been employed as a remedy attributed to its anti-inflammatory, antipyretic, antinociceptive, antidiabetic, neuroprotective, and antiparasitic properties. The aim of the present study was to investigate the antitumor activity of both the methanolic and aqueous extract of C. europaea. The effects of increasing concentrations of aqueous and methanolic extracts on human colorectal cancer HT-29 and HCT116 cell lines and human prostate cancer PC3 and DU145 cell lines were examined on cell proliferation using MTT assay and cell cycle analysis. The induction of apoptosis was also assessed by determining protein expression of caspase-3 and poly-ADP-ribose polymerase (PARP) cleavage by western blot. The methanolic extract of C. europaea exerted significant antiproliferative effects on HT-29 (IC50 values 73 µg/ml), HCT116 (IC50 values 67 µg/ml), PC3 (IC50 values 63 µg/ml) and DU145 cells (IC50 values 65 µg/ml) after 48 hr treatment. Further, incubation with methanolic extract of C. europaea induced cell cycle arrest in G1 phase and an apoptotic process for all treated cell lines. In conclusion, the present results suggest that C. europaea, exhibited that these natural compounds are significant apoptosis inducers which may have considerable potential for development of effective natural product anticancer agents.
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Apocynaceae , Neoplasias Colorrectales , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Apoptosis , Células HCT116 , Metanol , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
The treatment for hepatocellular carcinoma (HCC), a severe cancer with a very high mortality rate, begins with the surgical resection of the primary tumor. For metastasis or for tumors that cannot be resected, sorafenib, a multi-tyrosine protein kinase inhibitor, is usually the drug of choice. However, typically, neither resection nor sorafenib provides a cure. The drug discovery strategy for HCC therapy is shifting from monotherapies to combination regimens that combine an immuno-oncology agent with an angiogenesis inhibitor. Herbal formulas can be included in the combinations used for this personalized medicine approach. In this study, we evaluated the HCC anticancer efficacy of the new herbal formula, HO-1089. Treatment with HO-1089 inhibited HCC tumor growth by inducing DNA damage-mediated apoptosis and by arresting HCC cell replication during the G2/M phase. HO-1089 also attenuated the migratory capacity of HCC cells via the inhibition of the expression of EMT-related proteins. Biological pathways involved in metabolism and the mitotic cell cycle were suppressed in HO-1089-treated HCC cells. HO-1089 attenuated expression of the G2/M phase regulatory protein, PLK1 (polo-like kinase 1), in HCC cells. HCC xenograft mouse models revealed that the daily oral administration of HO-1089 retarded tumor growth without systemic toxicity in vivo. The use of HO-1197, a novel herbal formula derived from HO-1089, resulted in statistically significant improved anticancer efficacy relative to HO-1089 in HCC. These results suggest that HO-1089 is a safe and potent integrated natural medicine for HCC therapy.
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BACKGROUND: Ophiopogon japonicus (Thunb.) Ker Gawl., a well-known Chinese herb, has been used in traditional Chinese medicine for thousands of years. Extensive in vitro and in vivo studies have shown that O. japonicus and its active compounds exhibit potential anticancer effects in a variety of cancer cells in vitro and suppress tumor growth and metastasis without causing serious toxicity in vivo. PURPOSE: This review aims to systemically summarize and discuss the anticancer effects and the underlying mechanisms of O. japonicus extracts and its active compounds. METHODS: The review is prepared following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Various scientific databases including Web of Science, PubMed, Scopus, and Chinese National Knowledge Infrastructure were searched using the keywords: Ophiopogon japonicus, tumor, cancer, carcinoma, content, pharmacokinetics, and toxicity. RESULTS: O. japonicus extracts and the active compounds, such as ruscogenin-1-O-[ß-d-glucopyranosyl(1â2)][ß-d-xylopyranosyl(1â3)]-ß-d-fucopyranoside (DT-13), ophiopogonin B, and ophiopogonin D, exert potential anticancer effects, including the induction of cell cycle arrest, activation of apoptosis and autophagy, and inhibition of metastasis and angiogenesis. In addition, the mechanisms underlying these effects, as well as the pharmacokinetics, toxicity and clinical utility of O. japonicus extracts and active compounds are discussed. Furthermore, this review highlights the research and application prospects of these compounds in immunotherapy and combination chemotherapy. CONCLUSIONS: The traditional herb O. japonicus and its phytochemicals could be safe and reliable anticancer drug candidates, alone or in combination with chemotherapeutic drugs. We hope that this review, which highlights the anticancer properties of O. japonicus, will contribute to drug optimization, therapeutic development, and future studies on cancer therapies based on this medicinal plant.
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Medicamentos Herbarios Chinos , Ophiopogon , Medicamentos Herbarios Chinos/química , Ophiopogon/química , Medicina Tradicional China , FitoquímicosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fu Fang Gang Liu (FFGL) is an effective formula for treating wart proliferation caused by human papillomavirus (HPV) infection and has the potential to treat HPV-related cancers. However, scientific evidence of its anti-tumor activity against cervical cancer, the most common cancer caused by HPV, is lacking. AIM OF THE STUDY: To clarify the anti-tumor effect of an FFGL aqueous extract on human cervical cancer and its possible mechanism of cell cycle arrest in HeLa cells. MATERIALS AND METHODS: The anti-proliferative effect of FFGL on cervical cancer cells was assessed using the cell counting kit-8 assay. The proportion of apoptotic cells, cell cycle distribution, and cell division rate were determined using flow cytometry. Quantitative proteomics was used to identify differentially expressed proteins after FFGL treatment, and bioinformatics analysis was used to identify key nodal proteins affected by FFGL. Immunofluorescence and western blot analyses were used to explore changes in the expression of related proteins in the cell cycle and DNA damage pathways to elucidate the potential mechanism of action of FFGL against HeLa cell proliferation. RESULTS: FFGL inhibited cervical cancer cell proliferation and caused cell cycle arrest. According to quantitative proteomics, CyclinB1 may play an important role in the anti-proliferative effect of FFGL on HeLa cells. Additional experiments showed that FFGL aqueous extract caused ATM-mediated DNA damage, further phosphorylated CHK2, led to the inactivation of Cdc25C, inhibited the activity of the CDK1/CyclinB1 complex, and resulted in cell cycle arrest. CONCLUSIONS: FFGL can inhibit cervical cancer cell proliferation. Furthermore, it can increase CDK1 phosphorylation, block the cell cycle by causing DNA damage, and inhibit HeLa cell proliferation.
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Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Células HeLa , Neoplasias del Cuello Uterino/patología , Proliferación Celular , ADN , ApoptosisRESUMEN
Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.
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Lesión Renal Aguda , COVID-19 , Diabetes Mellitus Experimental , Ratones , Animales , SARS-CoV-2 , COVID-19/complicaciones , Quercetina/farmacología , Diabetes Mellitus Experimental/complicaciones , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Ratones Endogámicos , Puntos de Control del Ciclo CelularRESUMEN
Coumaric acid is a phenolic compound found in medicinal plants. Its use has been reported in the treatment of inflammatory diseases, prevention of alterations induced by oxidative stress, as well as acetaminophen-induced hepatotoxicity. Thus, this study evaluated coumaric acid as a potential treatment for liver fibrosis. Cell proliferation was assessed by the trypan blue exclusion technique and the cytotoxicity of coumaric acid was performed using an LDH assay. Mechanisms of cell apoptosis were evaluated by flow cytometry. The expression of genes associated with apoptosis, cell cycle control, and fibrosis was assessed by qPCR. The production of lipid droplets was quantified by oil red staining. The experiments performed showed that the treatment with coumaric acid was able to reduce cell proliferation without causing cell cytotoxicity or apoptosis. Coumaric acid was able to inhibit the expression of cyclin D1 and CDK's (CDK2, CDK4, and CDK6), increasing p53 and p21, which could lead to cell cycle arrest. Treatment with coumaric acid was also able to revert the activated phenotype of GRX cells to their quiescent state. Thus, our results suggest that coumaric acid has a potential therapeutic effect against liver fibrosis.