RESUMO
BACKGROUND: This study evaluated the efficacy of tegafur-uracil for advanced oral cancer. METHODS: From January 2008 to December 2013, clinical data from 356 patients with stage III or IV oral squamous cell carcinoma who received curative surgical resection and postoperative concurrent chemoradiotherapy, treated with or without tegafur-uracil, were analyzed from a prospectively designed database. Tegafur-uracil was orally administered to 114 of the 356 patients. Disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) rates were studied. RESULTS: In our study, the 5-year OS (p = 0.0008), DFS (p = 0.0034), and DSS (p = 0.0029) rates were significantly better in the tegafur-uracil group than in the control group. Distant metastasis occurred in 16.28% of patients in the tegafur-uracil group and 45.28% in the control group (odds ratio 4.3). The distant metastasis rate in the tegafur-uracil group was significantly lower than the control group, indicating that administration of tegafur-uracil after curative surgical treatment and concurrent chemoradiotherapy prevented distant metastasis and improved the OS, DFS, and DSS rate. CONCLUSIONS: The result of tegafur-uracil treatment in patients with advanced oral cancer showed significant improvement in the 5-year OS, DFS, and DSS rate, while also showing a decreased distant metastasis rate. Tegafur-uracil treatment is a useful, effective, and well-tolerated anticancer treatment for advanced oral cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia/mortalidade , Quimioterapia Adjuvante/mortalidade , Neoplasias Bucais/mortalidade , Cuidados Pós-Operatórios , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/terapia , Prognóstico , Taxa de Sobrevida , Tegafur/administração & dosagem , Uracila/administração & dosagemRESUMO
Nasopharyngeal carcinoma (NPC) is a cancer that arises from the epithelium of the nasopharynx. Celastrol is a triterpene from traditional Chinese medicine, which demonstrates anti-proliferative activity in several cancer cell lines. However, the effect of celastrol on human NPC and the underlying mechanisms are not yet elucidated. The present study investigated whether celastrol induced apoptosis in human NPC cells, and the underlying molecular mechanisms were explored. Celastrol decreased the viability of HONE-1 and NPC-039 cells in a dose-dependent manner, and induced G1 and G2/M phase cell cycle arrest. The level of cleaved caspases-3, -8, and -9 and poly (ADP-ribose) polymerase 1 increased in cells treated with celastrol. There was an increase in active Bcl-2-like 11 isoform S, Bcl-2-associated X, Bcl-2 antagonist/killer and truncated BH3-interacting death antagonist, and the levels of the anti-apoptotic Bcl-2 and Bcl-2-like 1 decreased. Celastrol induced an increase in Fas, Fas-associated via death domain, TNF receptor superfamily members (TNRSF) 1A and 10B, and TNFRSF1A associated via death domain, and induced a dose-dependent reduction in mitochondrial membrane potential. Celastrol inhibited activation of mitogen-activated protein kinase (MAPK) 1/3 and 14, and induced MAPK 8/9 activation. The results indicated that celastrol induced apoptosis through the death receptor and the mitochondrial pathway in human NPC cells, and is a promising candidate in the development of drugs against NPC.
RESUMO
Nasopharyngeal carcinoma (NPC), a tumor arising from epithelial cells that cover the surface and line the nasopharynx, is a rare malignancy worldwide but is prevalent in certain geographical areas, such as Southern Asia (Taiwan, Hong Kong, Singapore, Malaysia, and Southern China) and North Africa. Despite advances in diagnostic techniques and improvements in treatment modalities, the prognosis of NPC remains poor. Therefore, an effective chemotherapy regimen that enhances tumor sensitivity to chemotherapeutics is urgently required. Nimbolide, derived from Azadirachta indica, has a wide range of beneficial effects, including anti-inflammatory and anticancer properties. The present study evaluated the antitumor activity of nimbolide in NPC cells and its underlying mechanisms. Our results revealed that the treatment of HONE-1 cells with nimbolide potently inhibited cell viability. Moreover, nimbolide led to cell cycle arrest, which subsequently activated caspase-3, -8, and -9 and poly (ADP-ribose) polymerase to induce cell apoptosis. Moreover, nimbolide induced Bik, Bax, and t-Bid expression in HONE-1 cells. The results indicated that nimbolide induces apoptosis through the modulation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways. Nimbolide induces apoptosis in human NPC cells and is a potential chemopreventive agent against NPC proliferation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2085-2092, 2017.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Limoninas/farmacologia , Carcinoma , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Carcinoma Nasofaríngeo , Neoplasias NasofaríngeasRESUMO
Oral cancer is one of the most common cancers in the world. Approximately 90% of oral cancers are subtyped to oral squamous cell carcinoma (OSCC). Despite advances in diagnostic techniques and improvement in treatment modalities, the prognosis remains poor. Therefore, an effective chemotherapy mechanism that enhances tumor sensitivity to chemotherapeutics is urgently needed. Methyl protodioscin (MP) is a furostanol bisglycoside with a wide range of beneficial effects, including anti-inflammatory and anti-cancer properties. The aim of the present study was to determine the antitumor activity of MP on OSCC and its underlying mechanisms. Our results show that treatment of OSCC cells with MP potently inhibited cell viability. Moreover, MP leading to cell cycle arrest at G2/M phase, which subsequently activates caspase-3, -8, -9 and PARP to induce cell apoptosis. Meanwhile, we also demonstrate that MP induces a robust autophagy in OSCC cells. The results indicate cathepsin S (CTSS) is involved in MP-induced apoptosis and autophagy by modulation of p38 MAPK and JNK1/2 pathways. These findings may provide rationale to combine MP with CTSS blockade for the effective treatment of OSCC.
Assuntos
Catepsinas/antagonistas & inibidores , Diosgenina/análogos & derivados , Sistema de Sinalização das MAP Quinases , Neoplasias Bucais/metabolismo , Saponinas/farmacologia , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Pontos de Checagem do Ciclo Celular/genética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diosgenina/química , Diosgenina/farmacologia , Humanos , Neoplasias Bucais/genética , Saponinas/químicaRESUMO
BACKGROUND AND PURPOSE: Oral cancer is a type of head and neck cancer that is characterized by cancerous tissue growth in the oral cavity. Andrographolide and dehydroandrographolide (DA) are the two principal components of Andrographis paniculata (Burm.f.) Nees and are the main contributors to its therapeutic properties. However, the pharmacological activities of DA remain unclear. EXPERIMENTAL APPROACH: In this study, we used wound closure assay and Boyden chamber assay to determine the effects of DA on oral cancer cell migration and invasion. KEY RESULTS: DA treatment significantly inhibited the migration and invasion abilities of SCC9 cells in vitro. Gelatin zymography and Western blotting results revealed that DA inhibited MMP-2 activity and reduced its protein levels. DA inhibited the phosphorylation of ERK1/2, p38, and JNK 1/2 in SCC9 cells. According to the mRNA levels detected using real-time PCR, DA inhibited MMP-2 expression in SCC9 cells. This inhibitory effect was associated with the upregulation of the TIMP-2 and downregulation of NF-κB, AP-1, and SP-1 expression. In addition, DA suppressed carcinoma-associated epithelial-mesenchymal transition in SCC9 cells. Finally, DA administration effectively suppressed MMP-2 expression and tumor metastases in the oral carcinoma xenograft mouse model in vivo. CONCLUSIONS & IMPLICATIONS: DA inhibits the invasion of human oral cancer cells and is a potential chemopreventive agent against oral cancer metastasis.
Assuntos
Diterpenos/farmacologia , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Metástase Neoplásica/prevenção & controle , Inibidores de Proteases/farmacologia , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Bucais/enzimologia , Neoplasias Bucais/metabolismoRESUMO
BACKGROUND: Polyphyllin G (also called polyphyllin VII), extract from rhizomes of Paris yunnanensis Franch, has been shown to have strong anticancer activities in a wide variety of human cancer cell lines. However, the underlying influences of autophagy in human oral squamous cell carcinoma (OSCC) remain unclear. METHODS: In this study, the roles of apoptosis and autophagy in polyphyllin G-induced death in human oral cancer cells were investigated. Moreover, the molecular mechanism of the anticancer effects of polyphyllin G in human oral cancer cells was investigated. RESULTS: The results revealed that polyphyllin G significantly inhibited cell proliferation in human oral cancer cells; it dose-dependently induced apoptosis in SAS and OECM-1 cells through caspase-3, -8, and -9 activation and poly (ADP-ribose) polymerase cleavage. In addition, changes were observed in Bcl-2 and proapoptosis-related protein expression in different human oral cancer cell lines. The expression of both LC3-II and beclin-1 was markedly increased, suggesting the induction of autophagy in polyphyllin G-treated oral cells. To further clarify whether polyphyllin G-induced apoptosis and autophagy depended on Akt/extracellular signal-regulated kinases (ERK)/c-Jun N-terminal kinases (JNK)/p38 mitogen-activated protein kinases (MAPK) signaling pathways, the cells were cotreated with inhibitors. The results demonstrated polyphyllin G-induced apoptosis in oral cells through the activation of ERK, Akt, p38 MAPK, and JNK, whereas ERK and JNK accounted for polyphyllin G-induced autophagy. CONCLUSION: This study is the first to demonstrate apoptosis and autophagy during polyphyllin G-induced cell death in human oral cancer cell lines. These results suggest that polyphyllin G is a promising candidate for developing antitumor drugs targeting human oral squamous cell carcinoma.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Melanthiaceae/química , Neoplasias Bucais/tratamento farmacológico , Saponinas/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Bucais/patologia , Extratos Vegetais/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Polyphyllin G (also call polyphyllin VII), extract from rhizomes of Paris yunnanensis Franch, has been demonstrated to have strong anticancer activities in a wide variety of human cancer cell lines. Previous studies found that Polyphyllin G induced apoptotic cell death in human hepatoblastoma cancer and lung cancer cells. However, the underlying mechanisms of autophagy in human nasopharyngeal carcinoma (NPC) remain unclear. In this study, Polyphyllin G can potently induced apoptosis dependent on the activations of caspase-8, -3, and -9 and the changes of Bcl-2, Bcl-xL and Bax protein expression in different human NPC cell lines (HONE-1 and NPC-039). The amount of both LC3-II and Beclin-1 was intriguingly increased suggest that autophagy was induced in Polyphyllin G-treated NPC cells. To further clarify whether Polyphyllin G-induced apoptosis and autophagy depended on AKT/ERK/JNK/p38 MAPK signaling pathways, cells were combined treated with AKT inhibitor (LY294002), ERK1/2 inhibitor (U0126), p38 MAPK inhibitor (SB203580), or JNK inhibitor (SP600125). These results demonstrated that Polyphyllin G induced apoptosis in NPC cells through activation of ERK, while AKT, p38 MAPK and JNK were responsible for Polyphyllin G-induced autophagy. Finally, an administration of Polyphyllin G effectively suppressed the tumor growth in the NPC carcinoma xenograft model in vivo. In conclusion, our results reveal that Polyphyllin G inhibits cell viability and induces apoptosis and autophagy in NPC cancer cells, suggesting that Polyphyllin G is an attractive candidate for tumor therapies. Polyphyllin G may promise candidate for development of antitumor drugs targeting nasopharyngeal carcinoma.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Saponinas/farmacologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno , Neoplasias Nasofaríngeas/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: Nasopharyngeal carcinoma (NPC) is known for its high incidence of neck lymph node metastasis, which represents poor prognosis. Nobiletin is a citrus polymethoxyflavonoid that suppresses tumor growth and metastasis, both of which depend on angiogenesis in previous studies. However, the effect of Nobiletin on human NPC cells metastasis has not been clearly clarified. RESEARCH DESIGN AND METHODS: In this study, we determine the effects of Nobiletin on the migration and invasion in NPC cells. RESULTS: Nobiletin significantly inhibited migration/invasion capacities of HONE-1 and NPC-BM cell lines. The results of gelatin zymography and western blotting revealed that the activities and protein levels of the MMP-2 were inhibited by Nobiletin. Nobiletin also showed that inhibits phosphorylation of ERK1/2. Tests of the real-time PCR and promoter assays evaluated the inhibitory effects of Nobiletin on MMP-2 expression in human NPC cells. Nobiletin inhibits MMP-2 expression, up-regulating tissue inhibitor of metalloproteinase-2 and down-regulation of the transcription factors of NF-κB and activator protein 1 (AP-1) signaling pathways. Finally, an administration of Nobiletin effectively suppressed the tumor formation and metastasis in the NPC xenograft model in vivo. CONCLUSIONS: Nobiletin may have potential use as a chemo-preventive agent against nasopharyngeal cancer metastasis.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Movimento Celular/efeitos dos fármacos , Flavonas/farmacologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Animais , Carcinoma , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hispolon, a phenol compound isolated from Phellinus linteus (PL), possesses anti-inflammatory, antiproliferative, and antioxidant effects. However, the effects of hispolon on human nasopharyngeal carcinomas have yet to be evaluated. Here, the molecular mechanism by which hispolon anticancer effects in human nasopharyngeal carcinomas cells was investigated. The results showed that hispolon significantly inhibited cell proliferation of HONE-1 and NP-039 cell lines. Furthermore, hispolon induced apoptosis through caspases-3, -8, and -9 activations and PARP cleavage in dose- and time-dependent manner in HONE-1 and NP-039 cells. Moreover, hispolon also showed that increase phosphorylation of ERK1/2, p38 MAPK and JNK1/2 in dose- and time-dependent manner by western blot analysis. However, hispolon-induced activation of the caspase-3, -8 and -9 significantly abolished by inhibition of p38 MAPK and JNK1/2 specific inhibitors. In this study, we determine that the effects of hispolon on the apoptosis and related regulation mechanism in HONE-1 and NPC-039 cells takes place. Our findings revealed that hispolon may be a useful candidate as a chemotherapeutic agent for NPC therapy.
Assuntos
Apoptose/efeitos dos fármacos , Basidiomycota/química , Catecóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Nasofaríngeas/metabolismo , Carcinoma , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Carcinoma Nasofaríngeo , FosforilaçãoRESUMO
Tanshinone IIA (Tan IIA), an active phytochemical in the dried root of Salvia miltiorrhiza Bunge, has shown an antiproliferative activity on various human cancer cell lines including nasopharyngeal carcinoma cells. However, the effects of Tan IIA on human oral cancer cells are still unknown. This study aimed to investigate the antiproliferative effects of Tan IIA on human oral cancer KB cells and explored the possible underlying mechanism. Treatment of KB cells with Tan IIA suppressed cell proliferation/viability and induced cell death in a dose-dependent manner through sulforhodamine B colorimetric assay. Observation of cell morphology revealed the involvement of apoptosis in the Tan IIA-induced growth inhibition on KB cells. Cell cycle analysis showed a cell cycle arrest in G2/M phase on Tan IIA-treated cells. The dissipation of mitochondrial membrane potential observed by flow cytometry and the expression of activated caspases with the cleaved poly (ADP-ribose) polymerase under immunoblotting analysis indicated that Tan IIA-induced apoptosis in KB cells was mediated through the mitochondria-dependent caspase pathway. These observations suggested that Tan IIA could be a potential anticancer agent for oral cancer.
Assuntos
Abietanos/farmacologia , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Células KB , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Bucais/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismoRESUMO
BACKGROUND: Pure mucinous carcinoma (MC) is found in about 3.5% of all newly diagnosed breast cancer patients in Taiwan. MC is a relatively rare malignancy of breast cancer, and its nature, behaviors, treatment pattern and long-term follow-up are not well understood. The study aimed to investigate the incidence rate, treatment patterns, and prognostic factors of MC of the breast and the clinical long-term outcomes compared with infiltrating ductal carcinoma not otherwise specified (IDC) in the middle and south Taiwanese women. METHODS: Data from 93 patients with breast MC were retrospectively reviewed and the clinicopathologic characteristics and survival status were compared with those of 2,674 patients with IDC. RESULTS: The expression of hormonal receptor was higher in MC than those in IDC (P <0.001). MC also demonstrated lower Her2/neu gene over-expression (P = 0.023), less axillary lymph node involvement (P <0.0001), lymphovascular invasion (P <0.0001) and higher 10-year overall survival rate (P = 0.042), when compared with those of IDC. CONCLUSION: Our data confirm the less aggressive behavior of MC compared to IDC. MC showed favorable clinicopathologic characteristics in tumor grade, hormone receptor status and lymph node involvement in the middle and south Taiwanese women.
Assuntos
Adenocarcinoma Mucinoso/mortalidade , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Taiwan , Fatores de Tempo , Adulto JovemRESUMO
Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicinal prescription, has been used for the treatment of lymphadenopathy and solid tumors, and has shown therapeutic potential in several human malignant tumor cell lines. However, the efficacy and molecular mechanisms of action of SJKJT in human pancreatic cancer have not yet been elucidated. In the present study, we evaluated the cytotoxic effects of SJKJT on BxPC-3 human pancreatic carcinoma cells by MTT assay. The protein expression levels of myeloid cell leukemia 1 protein (Mcl-1), translationally controlled tumor protein (TCTP), tumor necrosis factor-α (TNFα), caspase-8, caspase-3, Bax and Bcl-2 family in the BxPC-3 cells were measured by western blot analysis. The cell cycle was analyzed by flow cytometry. The protein expression of caspase-3 was also detected by immunocytochemistry (ICC). The results revealed that SJKJT inhibited the proliferation of BxPC-3 cells in a time- and dose-dependent manner. The protein expression levels of TNF-α, caspase-8, caspase-3 and Bax increased in the BxPC-3 cells treated with SJKJT; however, the levels of Mcl-1, TCTP and Bcl-xL decreased. The results also demonstrated that SJKJT increased the percentage of BxPC-3 cells in the sub-G1 phase. In addition, ICC staining indicated that the protein expression of caspase-3 was upregulated in the BxPC-3 cells treated with SJKJT. These findings indicate that SJKJT inhibits the proliferation of BxPC-3 cells through the extrinsic and intrinsic pathway, inducing apoptosis in vitro. Our study, using BxPC-3 human pancreatic cancer cells, demonstrates that SJKJT has potential as a chemotherapeutic agent for the treatment of pancreatic cancer. Further sutdies are warranted to fully elucidate its mechanisms of action.
Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias Pancreáticas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Modelos Biológicos , Proteína Tumoral 1 Controlada por Tradução , Neoplasias PancreáticasRESUMO
Silent mating-type information regulation 2 homologue 1 (SIRT1), a member of the class III histone deacetylase (HDAC) family, is the mammalian ortholog of yeast Sir2. It has been reported to play a key role in a variety of physiological processes such as genomic stability, metabolism, neurogenesis and cell survival. The deacetylase function of SIRT1 has been suggested to play a role in prolonging the life of mammals. However, the suggested functions of SIRT1 as a potential tumor promoter have been challenged by observations of their respective downregulation and upregulation in various types of cancer. Breast cancer patients were included in the present study between 2007 and 2008. Their tumor tissues and paired normal breast tissues were collected and used for evaluation of the expression levels of SIRT1 and Ki67. The effects of SIRT1 on human breast cancer cell lines were also investigated. Immunohistochemistry showed that there is a high correlation between SIRT1 and Ki67 expression. Following treatment with sirtinol (inhibitor of SIRT1), the expression of the pro-survival protein Bcl-2 was markedly decreased in both MCF-7 and MDA-MB-231 cell lines, particularly in MDA-MB-231. Results of the present study revealed that inhibition of SIRT1 activity may be a promising chemotherapeutic strategy against breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Antígeno Ki-67/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Sirtuína 1/metabolismo , Benzamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Naftóis/farmacologia , Sirtuína 1/antagonistas & inibidoresRESUMO
Hepatic cancer remains a challenging disease and there is a need to identify new treatments. Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional medicinal prescription, has been used to treat lymphadenopathy and exhibits cytotoxic activity in many types of human cancer cells. Our previous studies revealed that SJKJT is capable of inhibiting colon cancer colo 205 cells by inducing autophagy and apoptosis. However, the effects and molecular mechanisms of SJKJT in human hepatocellular carcinoma have not been clearly elucidated. In the present study we evaluated the effects of SJKJT in human hepatic cellular carcinoma Hep-G2 cells. The cytotoxicity of SJKJT in Hep-G2 cells was measured by MTT assay. The cell cycles were analyzed by fluorescenceactivated cell sorting (FACS). The protein expression of translationally controlled tumor protein (TCTP), Mcl-1, Fas, TNF-α, Caspase-8, Caspase-3 and Bax in Hep-G2 cells treated with SJKJT was evaluated by western blotting. The protein expression of Caspase-3 was also detected by immunofluorescence staining. The results showed that SJKJT inhibits Hep-G2 cells in a time- and dosedependent manner. During SJKJT treatment for 48 and 72 h, the half-maximum inhibitory concentration (IC50) was 1.48 and 0.94 mg/ml, respectively. The FACS results revealed that increased doses of SJKJT were capable of increasing the percentage of cells in the sub-G1 phase. Immunofluorescence staining showed that Hep-G2 treated with SJKJT had increased expression of Caspase-3. The western blot results showed that the protein expression of Fas, TNF-α, Caspase-8, Caspase- 3 and Bax was upregulated, but that of TCTP and Mcl-1 was downregulated in Hep-G2 cells treated with SJKJT. In conclusion, these findings indicated that SJKJT inhibits Hep-G2 cells. One of the molecular mechanisms responsible for this may be the increased Fas, TNF-α, Caspase-8, Caspase- 3 and Bax expression; another mechanism may be via decreasing TCTP and Mcl-1 expression in order to induce apoptosis.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Caspases/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/farmacologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Células Hep G2 , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteína Tumoral 1 Controlada por Tradução , Receptor fas/metabolismoRESUMO
Pancreatic cancer remains a challenging disease worldwide. Tanshinone IIA (TanIIA) is one of the active constituents of Danshen (Radix Salviae miltiorrhizae). TanIIA has been hypothesized to inhibit numerous human cancer cells by various molecular mechanisms. However, the efficacy and molecular mechanism of TanIIA action in pancreatic cancer has not been well studied. In the present study, the cytotoxicity of TanIIA in human pancreatic cancer BxPC3 cells was evaluated by MTT assay. Cell cycle analysis of BxPC3 cells treated with TanIIA was performed by flow cytometry (FACS). Protein expression levels of TCTP, Mcl1, BclxL, Bax and Caspase3 in BxPC3 cells were measured by western blot analysis. The results revealed that TanIIA inhibited BxPC3 cells in a time and dosedependent manner. FACS analysis demonstrated that TanIIA increases the rate of subG1 phase. BxPC3 cells treated with TanIIA were identified to upregulate protein expression of Bax and Caspase3 and downregulate expression of TCTP, Mcl1 and BclxL. These results indicate that TanIIA may inhibit BxPC3 human pancreatic cancer cells through the induction of apoptosis by decreasing protein expression of TCTP, Mcl1 and BclxL and increasing Bax expression in vitro. The chemotherapeutic potential of TanIIA for human pancreatic cancer warrants further study.
Assuntos
Abietanos/toxicidade , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína bcl-X/metabolismo , Abietanos/química , Antineoplásicos Fitogênicos/química , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Salvia miltiorrhiza/química , Proteína Tumoral 1 Controlada por Tradução , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
Breast cancer is the leading cause of cancer-related deaths in women worldwide. Tanshinone IIA (Tan-IIA) is one of the pure compounds from Salviae miltiorrhizae radix (Danshen). Tan-IIA can inhibit human breast cancer cells but the molecular mechanisms are not well understood. Our previous study showed that Tan-IIA can inhibit hep-J5 human hepatocellular carcinoma cells through the endoplasmic reticulum (ER) stress-induced apoptotic pathway. In the present study, we evaluated the effects of Tan-IIA on BT-20 human breast cancer cells and assessed the involvement of the ER-stress-apoptotic pathway. The cytotoxicity of Tan-IIA in BT-20 cells was measured by the MTT assay. The cell cycles were analyzed by flow cytometry. The expression of ER stress-related proteins in BT-20 cells treated with Tan-IIA were evaluated by western blotting and immunocytochemical staining. These results showed that Tan-IIA can inhibit BT-20 cells and increase the sub-G1 phase in a time- and dose-dependent manner. Tan-IIA could increase the protein expression of caspase 12, GADD153, caspase 3, phospho-JNK, phospho-p38 and Bax, but decreased Bcl-xl and phospho-ERK expression in BT-20 cells. These findings indicate that Tan-IIA possesses therapeutic potential for human breast cancer BT-20 cells; one of the molecular mechanisms may be through inducing ER stress and the MAPK pathway to induce apoptosis and inhibit proliferation.
Assuntos
Abietanos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Caspase 12/genética , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Fator de Transcrição CHOP/genética , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
OBJECTIVE: This study aimed to investigate whether triple-negative breast cancer has a worse prognosis; here, we present the 10-year follow-up results of triple-negative breast cancer patients in Taiwan. METHODS: We identified 2858 breast cancer patients in Taiwan, of whom 416 (14.6%) had triple-negative breast cancer. Data used for analysis were derived from those breast cancer patients who were diagnosed between January 1996 and December 2006. RESULTS: In the Kaplan-Meier analysis, tumor subgroup (triple-negative breast cancer vs. non-triple-negative breast cancer) was a prognostic factor related to 10-year breast cancer death-specific survival and disease-free survival. The results of univariate analysis showed that tumor subgroup was a significant factor related to 10-year disease-free survival and breast cancer death-specific survival, as well as menopausal status, tumor size, lymph node, metastasis, grade, stage, estrogen receptor status, progesterone receptor status and her2/neu gene expression status. Similarly, the multivariate analysis also revealed that tumor subgroup was a significant factor related to 10-year breast cancer death-specific survival and disease-free survival, in addition to tumor size, lymph node, metastasis and grade. CONCLUSIONS: It was suggested that triple-negative breast cancer patients in Taiwan have worse 10-year survival. Notably, in node-positive patients, triple-negative breast cancer played a prognostic role in 10-year breast cancer death-specific survival.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/biossíntese , Receptores de Estrogênio/genética , Receptores de Progesterona/biossíntese , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , TaiwanRESUMO
The ability of tanshinone IIA (Tan-IIA) to inhibit the proliferation of human breast cancer cell lines in vitro and in vivo is well documented. However, the molecular mechanisms have not been fully elucidated. In the present study, MDA-MB-231 cells were treated with different concentrations of Tan-IIA for 48 h, followed by protein extraction for western blotting. For an in vivo study, MDA-MB-231 cells were implanted directly into female SCID mice which were divided randomly into three groups to be treated with vehicle, Tan-IIA (20 mg/kg) and Tan-IIA (60 mg/kg) every other day orally, with treatment starting 4 weeks after inoculation with the MDA-MB-231 cells. The results showed that Tan-IIA inhibited the proliferation of MDA-MB-231 cells and decreased the protein expression of LC3-II and Erb-B2 in vitro. Treatment with Tan-IIA (20 or 60 mg/kg) for 90 days resulted in a reduction in tumor size and weight compared to the control group. The protein expression of NF-κBp65 was reduced, while caspase-3 was up-regulated compared to the control group. These findings indicate that Tan-IIA inhibits tumor growth in a MDA-MB-231 xenograft animal model. One of the molecular mechanisms may be through a decrease in NF-κBp65 and an increase in caspase-3 expression.