RÉSUMÉ
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.
Sujet(s)
Tumeurs colorectales/traitement médicamenteux , Régulation négative/effets des médicaments et des substances chimiques , Fluorouracil/pharmacologie , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , microARN/biosynthèse , ARN tumoral/biosynthèse , Sesquiterpènes/pharmacologie , Tumeurs colorectales/génétique , Tumeurs colorectales/métabolisme , Tumeurs colorectales/anatomopathologie , Fluorouracil/agonistes , Cellules HCT116 , Humains , microARN/génétique , Protéines tumorales/biosynthèse , Protéines tumorales/génétique , ARN tumoral/génétique , Sesquiterpènes/agonistes , Voie de signalisation Wnt/effets des médicaments et des substances chimiques , Protéine Wnt3A/biosynthèse , Protéine Wnt3A/génétique , bêta-Caténine/biosynthèse , bêta-Caténine/génétiqueRÉSUMÉ
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.
Sujet(s)
5-Amino-imidazole-4-carboxamide/analogues et dérivés , Tumeurs colorectales/traitement médicamenteux , Fluorouracil/agonistes , Protein kinases/métabolisme , Ribonucléotides/pharmacologie , Protéine-1 de complémentation croisée de la réparation des lésions induites par les rayons X/métabolisme , AMP-activated protein kinase kinases , 5-Amino-imidazole-4-carboxamide/pharmacologie , 5-Amino-imidazole-4-carboxamide/usage thérapeutique , Antinéoplasiques/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Synergie des médicaments , Association de médicaments , Fluorouracil/pharmacologie , Fluorouracil/usage thérapeutique , Cellules HCT116 , Humains , Récepteurs CXCR4/génétique , Récepteurs CXCR4/métabolisme , Ribonucléotides/usage thérapeutique , Protéine-1 de complémentation croisée de la réparation des lésions induites par les rayons X/génétiqueRÉSUMÉ
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.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Fluorouracil/agonistes , O-(bêta-Hydroxyéthyl)rutosides/analogues et dérivés , Protéines proto-oncogènes c-bcl-2/antagonistes et inhibiteurs , Facteur de transcription STAT-3/antagonistes et inhibiteurs , Transduction du signal/effets des médicaments et des substances chimiques , Tumeurs de l'estomac/traitement médicamenteux , Animaux , Antimétabolites antinéoplasiques/composition chimique , Antimétabolites antinéoplasiques/usage thérapeutique , Antinéoplasiques d'origine végétale/usage thérapeutique , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Synergie des médicaments , Fluorouracil/usage thérapeutique , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Humains , O-(bêta-Hydroxyéthyl)rutosides/usage thérapeutique , Mâle , Souris nude , Facteur de transcription NF-kappa B/antagonistes et inhibiteurs , Facteur de transcription NF-kappa B/métabolisme , Protéines tumorales/antagonistes et inhibiteurs , Protéines tumorales/génétique , Protéines tumorales/métabolisme , Protéines proto-oncogènes c-bcl-2/génétique , Protéines proto-oncogènes c-bcl-2/métabolisme , Interférence par ARN , Répartition aléatoire , Facteur de transcription STAT-3/génétique , Facteur de transcription STAT-3/métabolisme , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/anatomopathologie , Charge tumorale/effets des médicaments et des substances chimiques , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
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.
Sujet(s)
Antimétabolites antinéoplasiques/agonistes , Carcinomes/traitement médicamenteux , Résistance aux médicaments antinéoplasiques/génétique , Fluorouracil/agonistes , Facteur de transcription NF-kappa B/analogues et dérivés , Facteur de transcription NF-kappa B/antagonistes et inhibiteurs , Tumeurs de l'estomac/traitement médicamenteux , Transport nucléaire actif/effets des médicaments et des substances chimiques , Transport nucléaire actif/génétique , Antimétabolites antinéoplasiques/toxicité , Apoptose/effets des médicaments et des substances chimiques , Apoptose/génétique , Sites de fixation/effets des médicaments et des substances chimiques , Sites de fixation/génétique , Carcinomes/génétique , Carcinomes/métabolisme , Caspase-3 , Caspases/effets des médicaments et des substances chimiques , Caspases/métabolisme , Synergie des médicaments , Fluorouracil/toxicité , Humains , Facteur de transcription NF-kappa B/métabolisme , Temps de réaction/effets des médicaments et des substances chimiques , Temps de réaction/génétique , Tumeurs de l'estomac/génétique , Tumeurs de l'estomac/métabolisme , Transcription génétique/effets des médicaments et des substances chimiques , Transcription génétique/génétique , Cellules cancéreuses en cultureRÉSUMÉ
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.