RESUMEN
Guava extracts purified from leaf and bark have many bio-active molecules with anti-cancer activities. In addition, lycopene-rich extracts obtained from red guava fruit can induce apoptosis in estrogen receptor-positive breast cancers. Triple-negative breast cancer (TNBC) lacks estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) and, therefore, hormone therapy and targeted therapy are not used in the clinic. The purpose of this study was to determine whether red guava fruit extracts can affect the proliferation of TNBC cells. In this study, cell viability was determined by using the MTT assay. Apoptosis and necrosis were analyzed using flow cytometry. Cleaved caspase-3 and PARP were analyzed by western blotting. We found that red guava extracts can, through caspase-3 activation and PARP cleavage signaling, induce apoptotic and necrotic death in TNBC cells. Our results thus show the therapeutic benefit of red guava extracts as a potential cancer treatment for TNBC in combination with doxorubicin or targeted therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Doxorrubicina/farmacología , Extractos Vegetales/farmacología , Psidium/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Praeruptorin C (PC) reportedly has beneficial effects in terms of antiinflammation, antihypertension, and antiplatelet aggregation, and it potentially has anticancer activity. However, the effect of PC on human non-small cell lung cancer (NSCLC) is largely unknown. Compared with the effects of praeruptorin A and praeruptorin B, we observed that PC significantly suppressed cell proliferation, colony formation, wound closure, and migration and invasion of NSCLC cells. It induced cell cycle arrest in the G0/G1 phase, downregulated cyclin D1 protein, and upregulated p21 protein. PC also significantly reduced the expression of cathepsin D (CTSD). In addition, the phosphorylation/activation of the ERK1/2 signalling pathway was significantly suppressed in PC-treated NSCLC cells. Cotreatment with PC and U0126 synergistically inhibited CTSD expression, cell migration, and cell invasion, which suggests that the ERK1/2 signalling pathway is involved in the downregulation of CTSD expression and invasion activity of NSCLC cells by PC. These findings are the first to demonstrate the inhibitory effects of PC in NSCLC progression. Therefore, PC may represent a novel strategy for treating NSCLC.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Catepsina D/metabolismo , Cumarinas/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Transducción de Señal/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Catepsina D/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Medicamentos Herbarios Chinos , Regulación de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Metástasis de la NeoplasiaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge, as known as Danshen, has used for the prevention and treatment of cardiovascular diseases clinically and anti-cancer activities. Salvianolic acid A (SAA), one of the most abundant ingredients, hydrophilic derivatives of Salvia miltiorrhiza Bunge, exerts a variety of pharmacological actions, such as anti-oxidative, anti-inflammatory and anti-cancer activities. However, the impact of SAA on nasopharyngeal carcinoma (NPC) invasion and metastasis remains unexplored. AIM OF THE STUDY: To investigate the potential of SAA to prevent migration and invasion on NPC cell. MATERIALS AND METHODS: MTT assay and Boyden chamber assay were performed to determine cell proliferation, migration and invasion abilities, respectively. The activity and protein expression of matrix metalloproteinase-2 (MMP-2) were determined by gelatin zymography and western blotting. RESULTS: Here, we showed that SAA considerably suppressed the migrative and invasive activity of human NPC cells but not rendered cytotoxicity. In SAA-treated NPC cells, the activity and expression of matrix metalloproteinase-2 (MMP-2), a key regulator of cancer cell invasion, were reduced. Additionally, the presence of high concentrations of SAA dramatically abolished the activation of focal adhesion kinase (FAK) and moderately inhibited the phosphorylation of Src and ERK in NPC cells. CONCLUSIONS: Our results demonstrated that SAA inhibited the migration and invasion of NPC cells, accompanied by downregulation of MMP-2 and inactivation of FAK, Src, and ERK pathways. These findings indicate a usefulness of SAA on restraining NPC invasion and metastasis.
Asunto(s)
Antineoplásicos/farmacología , Ácidos Cafeicos/farmacología , Lactatos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Humanos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Invasividad NeoplásicaRESUMEN
Aim: Sulfasalazine (SSZ) displayed anti-cancer activities. Vitamin E succinate (VES) could inhibit cell growth in various cancer cells. However, chemical therapies were often not useful for triple-negative breast cancer cells (TNBCs) treatment. Here, this study investigated the anti-cancer effects and the mechanisms on TNBCs under combination treatment with SSZ and VES. Methods: Cell viability was analyzed by using the MTT assay. The H2O2 levels were determined by using lucigenin-amplified chemiluminescence method. In addition, caspase and MAPs signals were studied by using western blotting. Results: Low-dose VES antagonized the SSZ-induced cytotoxicity effects while high-dose VES promoted the SSZ-induced cytotoxicity effects on TNBCs. In addition, SSZ alone treatment activated both caspase-3 and ERK signals, however, VES alone treatment only activated JNK signals. On the other hand, activation of caspase-3, JNK, and ERK were found in SSZ plus VES-treated cells. Conclusion: Combined SSZ and VES has synergistic or antagonistic cytotoxic effects depending on VES concentration. In addition, different cytotoxic signals are induced on SSZ-treated, VES-treated and SSZ plus VES-treated cells.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Sulfasalazina/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , alfa-Tocoferol/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quinasas MAP Reguladas por Señal Extracelular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Peróxido de Hidrógeno/aislamiento & purificación , MAP Quinasa Quinasa 4/genética , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Triplenegative breast cancers (TNBCs) lack the estrogen receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Therefore, hormone or targeted therapies are not effective in the treatment of TNBC and thus the development of novel therapeutic strategies is crucial. Methotrexate (MTX), a folate antagonist, has been used in the treatment of various types of cancer; however, the anticancer effects of MTX treatment on breast cancer have thus far been ineffective. Vitamin E variants and derivatives have been applied for cancer therapy. Previous studies have indicated that vitamin E variants and derivatives exert distinct anticancer effects on different types of cancer. However, whether MTX plus vitamin E variants or its derivatives can inhibit TNBC remains unclear. The aim of the present study was to examine the anticancer effects and mechanisms of action of MTX in combination with vitamin E variants (αtocopherol) and derivatives (αtocopherol succinate) on TNBC. In the present study, MTT assay and western blot analysis were used to determine the cell survival rates and protein levels. The results demonstrated that combination treatment with MTX and αtocopherol suppressed TNBC cell proliferation. In addition, various concentrations of MTX exerted distinct cytotoxic effects on αtocopherol succinatetreated cells. Furthermore, highdose MTX enhanced αtocopherol succinateinduced anticancer activity; however, lowdose MTX inhibited αtocopherol succinateinduced anticancer activity. The present study also demonstrated that caspase3 activation and poly(adenosine diphosphateribose) polymerase cleavage were observed in the αtocopherol succinate/MTXtreated cells. In conclusion, the findings of the present study demonstrated that highdose MTX enhanced anticancer activity in αTOStreated TNBC, while lowdose MTX reduced anticancer activity in αTOStreated TNBC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Metotrexato/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , alfa-Tocoferol/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Humanos , Metotrexato/uso terapéutico , alfa-Tocoferol/uso terapéuticoRESUMEN
Acetaminophen (APAP) is an analgesic and antipyretic agent primarily used in the clinical setting. However, high doses of APAP can cause oxidative stress. Guavas have been reported to provide antiinflammatory, antimicrobial, antioxidative and antidiarrheal functions. In addition, guavas have been reported to prevent renal damage due to progression of diabetes mellitus. Therefore, the aim of the present study was to investigate whether guavas can reduce APAPinduced renal cell damage. In the present study, extracts from guavas were obtained and added to APAPtreated renal tubular endothelial cells. The present results demonstrated that APAP induces cytotoxicity in renal tubular endothelial cells, while guava extracts inhibited this cytotoxicity. In addition, the study demonstrated that the protective effects of guava extracts against APAPinduced cytotoxicity may be associated with inhibition of oxidative stress and caspase3 activation.
Asunto(s)
Acetaminofén/farmacología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Frutas/química , Túbulos Renales/citología , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Psidium/química , Animales , Supervivencia Celular/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , RatasRESUMEN
Retinoic acid (RA), vitamin D and 12-Otetradecanoyl phorbol-13-acetate (TPA) can induce HL-60 cells to differentiate into granulocytes, monocytes and macrophages, respectively. Similar to RA and vitamin D, ascorbic acid also belongs to the vitamin family. Highdose ascorbic acid (>100 µM) induces HL60 cell apoptosis and induces a small fraction of HL60 cells to express the granulocyte marker, CD66b. In addition, ascorbic acid exerts an antioxidative stress function. Oxidative stress is required for HL60 cell differentiation following treatment with TPA, however, the effect of ascorbic acid on HL60 cell differentiation in combination with TPA treatment remains to be fully elucidated. The aim of the present study was to investigate the cellular effects of ascorbic acid treatment on TPA-differentiated HL-60 cells. TPA-differentiated HL-60 cells were used for this investigation, this study and the levels of cellular hydrogen peroxide (H2O2), caspase activity and ERK phosphorylation were determined following combined treatment with TPA and ascorbic acid. The results demonstrated that lowdose ascorbic acid (5 µM) reduced the cellular levels of H2O2 and inhibited the differentiation of HL60 cells into macrophages following treatment with TPA. In addition, the results of the present study further demonstrated that lowdose ascorbic acid inactivates the ERK phosphorylation pathway, which inhibited HL60 cell differentiation following treatment with TPA.
Asunto(s)
Ácido Ascórbico/farmacología , Diferenciación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Peróxido de Hidrógeno/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HL-60 , Humanos , Macrófagos , FosforilaciónRESUMEN
Aristolochic acid (AA) is a component of Chinese medicinal herbs, including asarum and aristolochia and has been used in Traditional Chinese Medicine for a long time. Recent studies found that AA has a cytotoxic effect resulting in nephropathy. These studies indicated that AAinduced cytotoxicity is associated with increases in oxidative stress and caspase3 activation. The present study further demonstrated that AA mainly elevates the H2O2 ratio, leading to increases in oxidative stress. Furthermore, the results indicated that AA induces cell death can via caspasedependent and independent pathways. It is desirable to identify means of inhibiting AAinduced renal damage; therefore, the present study applied an antioxidative nutrient, vitamin C, to test whether it can be employed to reduce AAinduced cell cytotoxicity. The results showed that vitamin C decreased AAinduced H2O2 levels, caspase3 activity and cytotoxicity in renal tubular cells. In conclusion, the present study was the first to demonstrate that AAinduced increases of the H2O2 ratio resulted in renal tubular cell death via caspasedependent and independent pathways, and that vitamin C can decrease AAinduced increases in H2O2 levels and caspase3 activity to attenuate AAinduced cell cytotoxicity.
Asunto(s)
Apoptosis/efectos de los fármacos , Ácidos Aristolóquicos/toxicidad , Ácido Ascórbico/farmacología , Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Estrés Oxidativo , Animales , Aristolochia/química , Asarum/química , Caspasa 3/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/toxicidad , Peróxido de Hidrógeno/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , RatasRESUMEN
Methotrexate (MTX) has been widely used for rheumatoid arthritis therapy for a long time. MTX is also used as an anticancer drug for various tumors. However, many studies have shown that high-dose MTX treatment for cancer therapy may cause liver and renal damage. Alhough the mechanisms involved in MTX-induced liver and renal damage require further research, many studies have indicated that MTX-induced cytotoxicity is associated with increases in oxidative stress and caspase activation. In order to reduce MTX-induced side-effects and increase anticancer efficiency, currently, combination treatments of low-dose MTX and other anticancer drugs are considered and applied for various tumor treatments. The present study showed that MTX induces increases in H2O2 levels and caspase-9/-3 activation leading to cell death in hepatocellular carcinoma Hep3B cells. Importantly, this study is the first to demonstrate that vitamin C can efficiently aid low-dose MTX in inducing cell death in Hep3B cells. Therefore, the present study provides a possible powerful therapeutic method for tumors using a combined treatment of vitamin C and low-dose MTX.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Ácido Ascórbico/farmacología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metotrexato/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Oxígeno/metabolismoRESUMEN
BACKGROUND: The survival rate of malignant tumors, and especially hepatocellular carcinoma (HCC), has not improved primarily because of uncontrolled metastasis. In our previous studies, we have reported that Terminalia catappa leaf extract (TCE) exerts antimetastasis effects on HCC cells. However, the molecular mechanisms of urokinase-type plasminogen activator (u-PA) in HCC metastasis have not been thoroughly investigated, and remain poorly understood. METHODS: The activities and protein levels of u-PA were determined by casein zymography and western blotting. Transcriptional levels of u-PA were detected by real-time PCR and promoter assays. RESULTS: We found that treatment of Huh7 cells with TCE significantly reduced the activities, protein levels and mRNA levels of u-PA. A chromatin immunoprecipitation (ChIP) assay showed that TCE inhibited the transcription protein of nuclear factors SP-1 and NF-κB. TCE also did inhibit the effects of u-PA by reducing the phosphorylation of ERK1/2 pathway. CONCLUSIONS: These results show that u-PA expression may be a potent therapeutic target in the TCE-mediated suppression of HCC metastasis.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Terminalia/química , Activador de Plasminógeno de Tipo Uroquinasa/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/fisiopatología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatología , FN-kappa B/genética , FN-kappa B/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Hepatitis B virus (HBV) infection accounts for over a half of cases of hepatocellular carcinoma (HCC), the most frequent malignant tumor of the liver. HBV-encoded X (HBx) plays critical roles in HBV-associated hepatocarcinogenesis. However, it is unclear whether and how HBx regulates the expression of epidermal growth factor receptor (EGFR), an important gene for cell growth. Therefore, the study aimed to investigate the association between HBx and EGFR expression. In this study, we found that HBx upregulates miR-7 expression to target 3'UTR of EGFR mRNA, which in turn results in the reduction of EGFR protein expression in HCC cells. HBx-mediated EGFR suppression renders HCC cells a slow-growth behavior. Deprivation of HBx or miR-7 expression or restoration of EGFR expression can increase the growth rate of HCC cells. Our data showed the miR-7-dependent EGFR suppression by HBx, supporting an inhibitory role of HBx in the cell growth of HCC. These findings not only identify miR-7 as a novel regulatory target of HBx, but also suggest HBx-miR-7-EGFR as a critical signaling in controlling the growth rate of HCC cells.
RESUMEN
RC-RNase exerts anti-cancer effects on many tumors. However, the mechanisms by which RC-RNase induces cytotoxicity in different tumor cells are unclear. Currently, estrogen receptor (ER)-positive and negative breast tumors are treated with RC-RNase. Our data demonstrate that RC-RNase induces cell death on ER-positive but not on ER-negative breast tumors. This study also shows that down-regulation of ER and Bcl-2 is found on RC-RNase-treated ER-positive breast tumors. Additionally, Bcl-2 overxpression can prevent ER-positive breast tumors from cell death treated with RC-RNase. In summary, this study demonstrates that RC-RNase-induced cell death of ER-positive breast tumors is through regulation of ER and Bcl-2.
Asunto(s)
Proteínas Anfibias/farmacología , Neoplasias de la Mama/patología , Carcinoma/patología , Endorribonucleasas/farmacología , Genes bcl-2/efectos de los fármacos , Receptores de Estrógenos/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Evaluación Preclínica de Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Receptores de Estrógenos/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Epigenetic alteration of DNA methylation plays an important role in the regulation of gene expression associated with chemosensitivity of human hepatocellular (HCC) carcinoma cells. With the aim of improving the chemotherapeutic efficacy for HCC, the effect of the naturally occurring compound n-butylidenephthalide (BP), which is isolated from a chloroform extract of Angelica sinensis, was investigated. In both HepG2 and J5 HCC cell lines, a synergistic antiproliferative effect was observed when a low dosage of BP was combined with the chemotherapeutic drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU is an alkylating agent, and it prompts us to examine one of DNA repair genes, O(6)-methylguanine methyltransferase (MGMT). It was evident from methylation-specific polymerase chain reaction (PCR) analysis that BP/BCNU combined treatment caused a time- and concentration-dependent enhancement of MGMT promoter methylation. Overexpression of MGMT could abolish BP-induced growth inhibition in the J5 tumor cell line as measured by colony formation assay. When BP was combined with BCNU and administered, it showed significant antitumor effects in both HepG2 and J5 xenograft tumors as compared with the use of only one of these drugs. The BCNU-induced apoptosis and inhibited MGMT protein expression in HCC cells, both in vitro and in vivo, resulting from the combination treatment of BP and BCNU suggest a potential clinical use of this compound for improving the prognosis for HCCs.