RESUMO
Colorectal carcinoma is a common malignant tumor occurring in the alimentary system. Despite developments of modern medicine, developed resistance to 5-fluorouracil (5-FU) may lead to poor prognosis. Herein, we aimed to explore the effects of beta-elemene on colorectal carcinoma cells (HCT116 and HT29) as well as the underlying mechanisms. Beta-elemene reduced cell viability and induced apoptosis in HCT116 and HT29 cells. Increased apoptosis following beta-elemene exposure was due to enhanced sensitivity to 5-FU through down-regulating miR-191. Expression of key kinases, including Wnt3a, and ß-catenin, were down-regulated by beta-elemene through a miR-191 mechanism. Moreover, beta-elemene might improve resistance of colorectal carcinoma cells to 5-FU by down-regulating miR-191, thereby inhibiting the Wnt/ß-catenin pathway.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/biossíntese , RNA Neoplásico/biossíntese , Sesquiterpenos/farmacologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Fluoruracila/agonistas , Células HCT116 , Humanos , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Neoplásico/genética , Sesquiterpenos/agonistas , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt3A/biossíntese , Proteína Wnt3A/genética , beta Catenina/biossíntese , beta Catenina/genéticaRESUMO
Colorectal cancer (CRC) is one of the leading causes of cancer mortality and 5-Fluorouracil (5-FU) is the most common chemotherapy agent of CRC. A high level of X-ray repair cross complementing group 1 (XRCC1) in cancer cells has been associated with the drug resistance occurrence. Moreover, the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been indicated to regulate the cancer cell survival. Thus, this study was aimed to examine whether XRCC1 plays a role in the 5-FU/AMPK agonist (AICAR)-induced cytotoxic effect on CRC and the underlying mechanisms. Human HCT-116 colorectal cells were used in this study. It was shown that 5-FU increases the XRCC1 expression in HCT-116 cells and then affects the cell survival through CXCR4/Akt signaling. Moreover, 5-FU combined with AICAR further result in more survival inhibition in HCT-116 cells, accompanied with reduced CXCR4/Akt signaling activity and XRCC1 expression. These results elucidate the role and mechanism of XRCC1 in the drug resistance of HCT-116 cells to 5-FU. We also demonstrate the synergistic inhibitory effect of AMPK on 5-FU-inhibited HCT-116 cell survival under the 5-FU and AICAR co-treatment. Thus, our findings may provide a new notion for the future drug regimen incorporating 5-FU and AMPK agonists for the CRC treatment.
Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/agonistas , Proteínas Quinases/metabolismo , Ribonucleotídeos/farmacologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Aminoimidazol Carboxamida/farmacologia , Aminoimidazol Carboxamida/uso terapêutico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Células HCT116 , Humanos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Ribonucleotídeos/uso terapêutico , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genéticaRESUMO
Gastric cancer still presents a significant problem for public health worldwide. Troxerutin (TXN), a flavonoid present in tea, coffee, cereal grains, and a variety of fruits and vegetables, exhibits various pharmacological and biological activities in vitro and in vivo. We investigated the ability of TXN to reverse the in vitro and in vivo drug resistance of human gastric cancer cells, which were resistant to treatment of 5-Fluorouracil (5-FU). 5-Fu is a pyrimidine analog, which is widely used in the treatment of cancers. Here, we found the growth inhibitory effects of TXN on human gastric cancer cell, resistant to 5-FU. TXN and 5-FU co-treatment resulted in a dose-dependent suppression of the cell proliferation. Decreasing of phosphorylated signal transducers and activation of transcription 3 (STAT3) was included in suppression of p65 by TXN with 5-FU in combination. Additionally, the presence of TXN sensitized gastric cancer cells resistant to 5-FU to 5-FU-induced apoptosis by suppressing Bcl-2. The pro-apoptotic proteins of Bax and Bid were up-regulated, accompanied with Caspase cleavage, leading to apoptosis. Moreover, in mice xenograft models, the combined therapy inhibited tumor growth compared to the TXN or 5-FU treatment alone. Our data indicated a novel therapeutic strategy to potentiate 5-FU-induced anti-tumor effect in gastric cancer cells with resistance to 5-FU by TXN through suppression of p-STAT3/NF-κB (p65 and p50) and Bcl-2.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/agonistas , Hidroxietilrutosídeo/análogos & derivados , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidroxietilrutosídeo/uso terapêutico , Masculino , Camundongos Nus , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , Distribuição Aleatória , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
5-fluorouracil (5-FU) is used for the treatment of stomach and colon cancer, but many tumors are resistant to this chemotherapeutic agent. 5-FU induces apoptosis of several cancer cell lines, while some chemotherapeutic agents are known to activate the transcriptional factor NF-kappaB, which strongly suppresses apoptosis in vitro. In the present study, we investigated the relationship between activation of NF-kappaB and chemoresistance to 5-FU in human stomach cancer cell lines, NUGC3 (5-FU sensitive) and NUGC3/5FU/L (5-FU resistant). Treatment with 5-FU for 9-12 h caused activation of inducible NF-kappaB in NUGC3/5FU/L cells but not in NUGC3 cells. 5-FU also resulted in an increase in the number of TUNEL-positive cells and enhanced caspase-3 activity 3- to 5-fold in NUGC3 cells but not NUGC3/5FU/L cells. Moreover we also demonstrated that the inhibition of inducible NF-kappaB activation by using a NF-kappaB decoy could induce apoptosis and reduce chemoresistance against 5-FU. Our results suggest that 5-FU chemoresistance can be overcome by inhibition of inducible NF-kappaB activation, and that the use of the NF-kappaB decoy combined with 5-FU treatment is a new molecular and gene therapeutic strategy aimed at treatment of human stomach cancers resistant to 5-FU.
Assuntos
Antimetabólitos Antineoplásicos/agonistas , Carcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/agonistas , NF-kappa B/análogos & derivados , NF-kappa B/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Antimetabólitos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Apoptose/genética , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Carcinoma/genética , Carcinoma/metabolismo , Caspase 3 , Caspases/efeitos dos fármacos , Caspases/metabolismo , Sinergismo Farmacológico , Fluoruracila/toxicidade , Humanos , NF-kappa B/metabolismo , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Células Tumorais CultivadasRESUMO
The combination of 5-fluorouracil (5-FU) and leucovorin has been the unofficial "standard" therapy for patients with colorectal cancer for over a decade. Recently, however, a number of new agents targeted against the enzyme thymidylate synthase have been synthesized and are in various stages of development. The currently available thymidylate synthase inhibitors are discussed. Enormous efforts have been made over the years to improve the efficacy of 5-FU, the most popular of these agents. Biochemical modulation by leucovorin has been the most successful so far. Continuous infusion schedules also appear to be advantageous over bolus administration. However, marked intra- and interpatient variability, combined with nonlinear elimination kinetics and erratic oral bioavailability are relative limitations to further development of 5-FU. New oral 5-FU prodrugs such as UFT, S-1, and Capecitabine may help to overcome some of these difficulties. Eniluracil, a potent inhibitor of the enzyme dihydropyrimidine dehydrogenase, may also help by overcoming potential 5-FU resistance mechanisms, in addition to increasing its bioavailability. Of the antifolate-based inhibitors, Tomudex is in the most advanced stage of development. Similar efficacy with 5-FU and a convenient schedule may suggest a role in future combination regimens. It is quite likely that even the most optimal thymidylate synthase inhibition will have limitations in terms of clinical efficacy. Novel combinations of 5-FU or its analogs with agents that have different mechanisms of action (e.g., oxaliplatin, irinotecan) could provide important new opportunities for improving the outlook of patients with colorectal cancer.