Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.438
Filtrar
1.
Anticancer Res ; 40(11): 6265-6271, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109564

RESUMO

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. This study aimed to investigate the anticancer effect of the combination treatment of Ribociclib (LEE011) and 5-Fluorouracil (5-FU) on CRC cells. MATERIALS AND METHODS: HT-29 and SW480 cells were treated with LEE011, 5-FU, or the combination of LEE011 and 5-FU. Cell viability and cycle were investigated through 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and flow cytometry. The expression of cell cycle-related proteins was determined through western blot. RESULTS: The combined treatment of LEE011 with 5-FU synergistically reduced cell viability in HT-29 and SW480 cells. Specifically, it induced cell cycle arrest at the G1 phase, down-regulated the phosphorylation of retinoblastoma protein and the expression of p53. CONCLUSION: LEE011 exhibited potential as an effective therapeutic inhibitor for the combination treatment of CRC patients.


Assuntos
Aminopiridinas/farmacologia , Neoplasias Colorretais/patologia , Fluoruracila/farmacologia , Purinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos
2.
Nat Commun ; 11(1): 5321, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087710

RESUMO

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/ß-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/ß-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Fluoruracila/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Camundongos Transgênicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Organoides/efeitos dos fármacos , Organoides/metabolismo , Organoides/patologia , Pirazinas/administração & dosagem , Piridinas/administração & dosagem , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Proteína Wnt3/genética , Proteína Wnt3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Nanomedicine ; 15: 7791-7803, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116501

RESUMO

Background: The synergistic effect of nanomaterials and chemotherapeutics provides a novel strategy for the treatment of tumors. Silver nanotriangles (AgNTs) exhibited some unique properties in nanomedicine. Studies on the synergy of silver-based nanomaterials and anti-tumor drugs against gliomas are rare. Materials and Methods: Chitosan-coated AgNTs were prepared, followed by characterization using transmission electron microscopy, ultraviolet-visible spectroscopy and X-ray diffraction. The anti-glioma effect of cyclophosphamide (CTX), 5-fluorouracil (5-FU), oxaliplatin (OXA), doxorubicin (DOX) or gemcitabine (GEM) combined with AgNTs in different glioma cell lines (U87, U251 and C6) was assessed by the MTT assay to screen out a drug with the most broad-spectrum and strongest synergistic anti-glioma activity. The intracellular reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) and cell apoptosis were detected by flow cytometry. The possible underlying mechanisms of the synergy were further investigated with ROS scavenger and specific inhibitors of C-jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase 1/2 pathways. Results: The synthesized AgNTs were mainly triangular and truncated triangular with an average edge length of 125 nm. A synergistic anti-glioma effect of AgNTs combined with CTX was not observed, and the synergism between AgNTs and 5-FU was cell type-specific. AgNTs combined with OXA, DOX or GEM displayed synergistic effects in various glioma cell lines, and the combination of AgNTs and GEM showed the strongest synergistic activity. A decrease in cell viability, loss of the MMP and an increase in apoptosis rate induced by this synergy could be significantly attenuated by the ROS scavenger N-acetylcysteine and JNK inhibitor SP600125. Conclusion: Our results suggested that the combination of AgNTs and GEM possessed broad-spectrum and potent synergistic anti-glioma activity, resulting from cell apoptosis mediated by a ROS-dependent mitochondrial pathway in which JNK might be involved.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Glioma/patologia , Mitocôndrias/efeitos dos fármacos , Nanoestruturas/química , Prata/química , Prata/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Fluoruracila/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Anticancer Res ; 40(10): 5393-5397, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988858

RESUMO

BACKGROUND/AIM: We established a new patient-derived orthotopic xenograft (PDOX) model of gastric cancer liver metastasis and evaluated the efficacy of a novel combination chemotherapy, gemcitabine (GEM) plus 5-fluorouracil (5-FU), compared to a standard regimen of oxaliplatinum (L-OHP) plus 5-FU on the liver metastasis. MATERIALS AND METHODS: Patient-derived gastric cancer was established in nude mice from the patient' s surgical tumor specimen. A single tumor fragment was implanted in the liver of nude mice. The mice with tumors were treated by GEM plus 5-FU or L-OHP plus 5-FU. RESULTS: GEM plus 5-FU or L-OHP plus 5-FU significantly and similarly inhibited tumor growth on the liver compared to the untreated control (p=0.007, p=0.02, respectively). CONCLUSION: GEM plus 5-FU could be a novel future clinical alternative to L-OHP plus 5-FU in gastric cancer patients who cannot tolerate platinum drugs.


Assuntos
Desoxicitidina/análogos & derivados , Fluoruracila/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Oxaliplatina/farmacologia , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 40(10): 5611-5620, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988885

RESUMO

BACKGROUND/AIM: Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPC on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells. MATERIALS AND METHODS: PrPC negative and PrPC positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting. Sphere formation, cancer stem cell marker expression, migration, invasion, and drug resistance were analyzed. RESULTS: PrPC positive cells showed increased sphere formation capacity and increased expression of cancer stem cell markers compared to PrPC negative cells. In addition, PrPC positive cells showed increased migration, invasion and drug resistance compared to PrPC negative cells. Furthermore, knockdown of PrPC abolished these effects. CONCLUSION: PrPC expression is important in CRC cell behavior, such as sphere formation, migration, invasion, and drug resistance. PrPC is an important therapeutic target for the treatment of CRC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Proteínas Priônicas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/genética , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos
6.
Life Sci ; 259: 118255, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32818543

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies with a significant mortality rate. Despite the great advances in cancer treatment in the last few decades, effective treatment of CRC is still under challenge. One of the main problems associated with CRC treatment is the resistance of cancer cells to chemotherapy drugs. METHODS: Many studies have been carried out to identify CRC chemoresistance mechanisms, and shed light on the role of ATP-binding cassette transporters (ABC transporters), enzymes as thymidylate synthase, some signaling pathways, and cancer stem cells (CSC) in chemoresistance and failed CRC chemotherapies. Other studies have also been recently carried out to find solutions to overcome chemoresistance. Some of these studies have identified the role of miRNAs in chemoresistance of the CRC cells and the effective use of these micro-molecules to CRC treatment. RESULTS: Considering the results of these studies, more focus on miRNAs likely leads to a proper solution to overcome CRC chemoresistance. CONCLUSION: The current study has reviewed the related literature while discussing the efficacy of miRNAs as potential clinical tools for overcoming CRC chemoresistance and reviewing the most important chemoresistance mechanisms in CRC cells.


Assuntos
Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Int J Nanomedicine ; 15: 5417-5432, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801697

RESUMO

Introduction: Green-based materials have been increasingly studied to circumvent off-target cytotoxicity and other side-effects from conventional chemotherapy. Materials and Methods: Here, cellulose fibers (CF) were isolated from rice straw (RS) waste by using an eco-friendly alkali treatment. The CF network served as an anticancer drug carrier for 5-fluorouracil (5-FU). The physicochemical and thermal properties of CF, pure 5-FU drug, and the 5-FU-loaded CF (CF/5-FU) samples were evaluated. The samples were assessed for in vitro cytotoxicity assays using human colorectal cancer (HCT116) and normal (CCD112) cell lines, along with human nasopharyngeal cancer (HONE-1) and normal (NP 460) cell lines after 72-hours of treatment. Results: XRD and FTIR revealed the successful alkali treatment of RS to isolate CF with high purity and crystallinity. Compared to RS, the alkali-treated CF showed an almost fourfold increase in surface area and zeta potential of up to -33.61 mV. SEM images illustrated the CF network with a rod-shaped structure and comprised of ordered aggregated cellulose. TGA results proved that the thermal stability of 5-FU increased within the drug carrier. Based on UV-spectroscopy measurements for 5-FU loading into CF, drug loading encapsulation efficiency was estimated to be 83 ±0.8%. The release media at pH 7.4 and pH 1.2 showed a maximum drug release of 79% and 46%, respectively, over 24 hours. In cytotoxicity assays, CF showed almost no damage, while pure 5-FU killed most of the both normal and cancer cells. Impressively, the drug-loaded sample of CF/5-FU at a 250 µg/mL concentration demonstrated a 58% inhibition against colorectal cancer cells, but only a 23% inhibition against normal colorectal cells. Further, a 62.50 µg/mL concentration of CF/5FU eliminated 71% and 39% of nasopharyngeal carcinoma and normal nasopharyngeal cells, respectively. Discussion: This study, therefore, showed the strong potential anticancer activity of the novel CF/5-FU formulations, warranting their further investigation.


Assuntos
Celulose/química , Portadores de Fármacos/química , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Fluoruracila/farmacocinética , Células HCT116 , Humanos , Neoplasias Nasofaríngeas/tratamento farmacológico , Oryza/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
8.
Oncogene ; 39(36): 5825-5838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32753651

RESUMO

Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.


Assuntos
Carcinoma Ductal Pancreático/genética , Moléculas de Adesão Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Hedgehog/metabolismo , Oxigenases de Função Mista/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas/genética , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ilhas de CpG , Metilação de DNA , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Regiões Promotoras Genéticas , Transdução de Sinais
9.
Anticancer Res ; 40(8): 4505-4511, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727780

RESUMO

BACKGROUND/AIM: The expression of corticotropin-releasing hormone (CRH)-related peptides involved in stress response in colorectal cancer has been reported. We examined the involvement of CRH-related peptides in cellular stress caused by anticancer drugs in colorectal cancer. MATERIALS AND METHODS: Changes in the expression levels of CRH-related peptides and their receptors in HCT116, DLD-1, and SW480 cell lines after fluorouracil (5-FU) loading were evaluated. Effects of the receptor antagonist against DNA synthesis disorder caused by 5-FU and SN-38 were evaluated using the 3H-labeled deoxyribonucleoside incorporation assay. RESULTS: No changes in the mRNA expression levels of CRH-related peptides (UCN and UCN2) -and their receptors (CRHR1 and CRHR2) were observed. Addition of antagonists to cells with DNA synthesis disorder caused by 5-FU and SN-38 showed no differences in the incorporation of 3H-labeled deoxyribonucleoside. CONCLUSION: CRH-related peptides showed no effect on the stress response to anticancer drugs nor on DNA synthesis disorder in colorectal cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/genética , Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Irinotecano/farmacologia
10.
Yi Chuan ; 42(6): 577-585, 2020 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-32694116

RESUMO

Cancer cell line models are widely used for testing drug sensitivity and in screening for drug resistance markers. However, the general level of drug resistance in cancer cell lines is often ignored by researchers, making it difficult to apply many drug efficacy markers in clinical practice. In this study, we examined 48 colorectal cancer (CRC) cell lines to calculate the correlation coefficients between the IC50 values for 265 drugs. The general drug resistance evaluation index MIC50 was constructed using the median value of 265 drugs' IC50 values. Genes with positively correlated expression values and a MIC50 which rose to significance were selected for further study. To analyze the effect of general drug resistance on the response status and prognosis in CRC patients, the general drug resistance scoring model was established based on within-sample relative expression orderings of gene pairs. The results demonstrate that more than 99% of the IC50 correlation coefficients of 265 drugs were significantly positive (FDR<0.05), indicating that CRC cell lines possessed general drug resistance characteristics. Furthermore, we identified 602 general drug resistance related genes, and by using Metascape, we identified four functional modules closely related to tumor resistance. A scoring model of 5-FU-based general drug resistance levels consisting of 21 gene pairs was built. After performing χ 2 test, we found that the general drug resistance level in CRC patients was significantly correlated with the response information after accepting 5-FU-based combination drug therapy. Survival analysis showed that the low scoring cohort of patients had a better prognosis than the higher scoring cohort, indicating that the level of basic drug resistance was closely related to the prognosis and drug response status in these patients. These results provide basic theoretical support for further research on the mechanism of combined chemotherapy resistance and the individualized regimen of clinical drug use in patients with CRC.


Assuntos
Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Fluoruracila , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico
11.
Arch Oral Biol ; 117: 104825, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32622257

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effects of Lactobacillus reuteri applied locally or systemically with scaling and root planing (SRP) to the treatment of experimental periodontitis (EP) in rats treated with 5-fluorouracil. METHODS: A cotton ligature was installed on the molars of rats. The animals (n = 54) underwent chemotherapy and were divided into groups: SRP (n = 18), scaling and root planing only; LP (n = 18), SRP and 4 sessions of local probiotic (PRO); SP, SRP and 4 sessions of systemic PRO. The molar furcation area was submitted to histopathological, histometric of alveolar bone loss (ABL) and immunolabeling analysis after euthanasia at 7, 15 and 30 days. The data were submitted to statistical analysis (α = 5%). RESULTS: At 15 days ABL was higher in LP compared to SP. At 30 days, ABL was higher in LP compared to SRP and SP. Higher immunolabeling of TGF-ß1 was observed in LP and SP at 7 days compared to SRP (p < 0.05). Lower immunolabeling of OCN and higher immunolabeling of RANKL were observed at all periods in SRP compared to SP (p < 0.05). At 30 days, SRP showed lower immunolabeling of OPG compared to SP and LP (p < 0.05). In SP, lower immunolabeling was observed at 15 days compared at 30 days (p < 0.05). CONCLUSION: The ABL was similar among the groups treated with SRP associated or not to probiotic therapeutic, although the systemic use of Lactobacillus reuteri considerably reduced inflammation and favored periodontal tissues repair.


Assuntos
Raspagem Dentária , Lactobacillus reuteri , Periodontite , Aplainamento Radicular , Animais , Fluoruracila/farmacologia , Periodontite/terapia , Ratos
12.
Int J Nanomedicine ; 15: 3333-3346, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494133

RESUMO

Background and Objective: Cancer cells accumulate high concentrations of reactive oxygen species as a result of their faster and uninhibited metabolic activity. Cancer chemotherapeutic agents release an excess of severe adverse reactions as a result of targeting normal cells. This demands an improvement in targeted drug-delivery systems to selectively discharge anticancer drugs in the vicinity of such highly metabolically and mitotically active cells. Materials and Methods: Here, magnetic nanoparticles were synthesized by a traditional co-precipitation technique. Fe3O4@OA-CS-5-FLU-NPs were synthesized by an easy and rapid in situ loading method. The proposed Fe3O4@OA-CS-5-FLU-NPs were productively prepared as well as characterized by various spectroscopic and microscopic studies. Results: The targeted drug release profile of the Fe3O4@OA-CS-5-FLU-NPs was studied in the presence of ROS including H2O2 and pH induction. The released product, Fe3O4@OA-CS-5-FLU-NP, exhibited desirable levels of cytotoxicity and demonstrated morphological changes and inhibition of colony formation for A549 and HeLa S3 cancer cells. The IC50 values at 24 hours were 12.9 and 23 µg/mL, respectively. Conclusion: In summary, results from the MTT assay, fluorescence staining as well as colony formation assays, revealed that the Fe3O4@OA-CS-5-FLU-NPs were active and safe for anticancer biomedical applications. In summary, the present investigation provides a powerful nanostructured based system for improved cancer theranostics that should be further studied.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Compostos Férricos/química , Nanopartículas de Magnetita/química , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Nanopartículas de Magnetita/ultraestrutura , Neoplasias/patologia , Ácido Oleico/química , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios X
13.
Exp Mol Pathol ; 115: 104481, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32497621

RESUMO

Competing endogenous RNA (ceRNA) networks consisted of long non-coding RNA (lncRNA), microRNA (miRNA) and mRNAs have aroused great interests recently. The current study aims to probe the mechanisms of lncRNA TMPO-AS1 in ovarian cancer (OC) development. A 5-fluorouracil (5-FU)-resistant subline of OC SKOV3 cells was developed, and differentially expressed lncRNAs in OC tissues and SKOV3 cells were analyzed. The miRNAs, genes and signaling pathways interacted with TMPO-AS1 were predicted and validated. TMPO-AS1 and the validated miRNA were inhibited to analyze their roles in malignant behaviors and 5-FU resistance of OC cells. In vivo studies were performed by inducing xenograft tumors in nude mice. Consequently, TMPO-AS1 was highly expressed in OC tissues and SKOV3 cells. TMPO-AS1 regulated transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) through sponging miR-200c in OC cells, during which the PI3K/Akt signaling pathway was activated. Silenced TMPO-AS1 and over-expressed miR-200c inhibited epithelial-mesenchymal transition (EMT), invasion, migration and 5-FU resistance of OC cells. This study demonstrated that silencing of TMPO-AS1 might attenuate OC progression through inhibiting the invasion, metastasis and drug resistance of OC cells via the miR-200c/TMEFF2 network and the disruption of the PI3K/Akt signaling pathway.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Redes Reguladoras de Genes , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/genética , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Metástase Neoplásica , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
Gulf J Oncolog ; 1(33): 84-86, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32476656

RESUMO

BACKGROUND: Toxic leukoencephalopathy predominantly affect white matter of the brain parenchyma. Patient presents either in acute, subacute or chronic phase. The clinical presentation may vary, ranging from mild cognitive impairment to severe neurological dysfunction. It can also mimic psychiatric illness. CASE REPORT: A 50-year-old woman was diagnosed with locally advanced carcinoma buccal mucosa. She was planned for Neoadjuvant chemotherapy consisting of Docetaxel, Cisplatin, 5-FU (TPF). During 3rd day of 3rd cycle of 5-fluorouracil (5FU) infusion, patient developed hypoactive delirium and later became comatose state of drowsiness, with Glasgow Coma Scale (GCS) was 5. There was no previous history for the same. Hence, the infusion was stopped. Patient was evaluated with NCCT head. No abnormality was seen on CT scan. MRI brain was done and it showed diffusion restriction with T2 / FLAIR hyper intensities in bilateral centrum semiovale, white matter of bilateral parietal region and in corpus callosum. Patient received symptomatic care, nutrition by ryles tube during this period and she started to improve after 1st week of onset of symptoms. After 3 weeks, MRI was repeated and there was complete resolution of previous findings. CONCLUSIONS: Development of neurological symptoms during 5FU infusion is a rare entity. Henceforth, occurrence of toxic leukoencephalopathy should be kept in mind. Diffusion weighted imaging play an important role in both acute episode of toxic encephalopathy and in follow up.


Assuntos
Fluoruracila/uso terapêutico , Leucoencefalopatias/tratamento farmacológico , Feminino , Fluoruracila/farmacologia , Humanos , Pessoa de Meia-Idade
15.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188387, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32579889

RESUMO

Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3rd leading cause of cancer-related deaths in the United States. Cooperation between the tumor cells and the immune system leads to the immune escape and eventual establishment of the tumor. For more than 20 years, sincere efforts have been made to intercept the tumor-immune crosstalk and identify the probable therapeutic targets for breaking self-tolerance toward tumor antigens. However, the success of these studies depends on detailed examination and understanding of tumor-immune cell interactions, not only in the primary tumor but also at distant systemic niches. Innate and adaptive arms of the immune system sculpt tumor immunogenicity, where they not only aid in providing an amenable environment for their survival but also act as a driver for tumor relapse at primary or distant organ sites. This review article highlights the key events associated with tumor-immune communication and associated immunosuppression at both local and systemic microenvironments in PDAC. Furthermore, we discuss the approaches and benefits of targeting both local and systemic immunosuppression for PDAC patients. The present articles integrate data from clinical and genetic mouse model studies to provide a widespread consensus on the role of local and systemic immunosuppression in undermining the anti-tumor immune responses against PDAC.


Assuntos
Carcinoma Ductal Pancreático/terapia , Imunoterapia/métodos , Neoplasias Pancreáticas/terapia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Vacinas Anticâncer/administração & dosagem , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Modelos Animais de Doenças , Intervalo Livre de Doença , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Imunidade Inata/efeitos dos fármacos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Excisão de Linfonodo , Linfonodos/imunologia , Linfonodos/patologia , Linfonodos/cirurgia , Camundongos , Camundongos Transgênicos , Terapia Neoadjuvante/métodos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Baço/imunologia , Baço/patologia , Baço/cirurgia , Esplenectomia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/transplante , Transplante Autólogo/métodos
16.
Anticancer Res ; 40(6): 3247-3254, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487619

RESUMO

BACKGROUND/AIM: 5-Fluorouracil (5-FU) is an anticancer drug commonly used to treat gastric cancer; however, continuous 5-FU chemotherapy causes drug resistance. MATERIALS AND METHODS: We established five sublines of 5-FU-resistant AGS gastric cancer cells to investigate changes that may have occurred in the development of 5-FU resistance. Drug resistance to other chemotherapeutic reagents, proliferation, cell-cycle changes, and wound healing ability were assessed for each subline. RESULTS: Retarded cell growth, G0/G1 phase arrest, up-regulation of p57, and down-regulation of cyclin D1 were commonly observed in all five sublines. Resistance to paclitaxel and cisplatin was also observed in most of the sublines. CONCLUSION: Our data support the notion that G0/G1 arrest due to changes in p57 and cyclin D1 expression may confer drug resistance, while EMT seems non-essential to 5-FU resistance in AGS gastric carcinoma cells.


Assuntos
Fluoruracila/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Antimetabólitos Antineoplásicos/farmacologia , Ciclo Celular/fisiologia , Resistencia a Medicamentos Antineoplásicos , Humanos
17.
Cancer Sci ; 111(9): 3142-3154, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32536012

RESUMO

Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5-fluorouracil (5-FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5-FU resistance. Some are disease-specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5-FU. In this review, we construct a global outline of different mechanisms from disruption of 5-FU-metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial-mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antimetabólitos Antineoplásicos/metabolismo , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Fluoruracila/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Estresse Oxidativo/efeitos dos fármacos , Timidilato Sintase/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
18.
Nat Struct Mol Biol ; 27(6): 529-532, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-222247

RESUMO

The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (Mpro). Here, the X-ray crystal structure of Mpro in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 µM) and is a promising lead compound to develop new antiviral treatment for COVID-19.


Assuntos
Betacoronavirus/enzimologia , Cisteína Endopeptidases/química , Fluoruracila/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Animais , Betacoronavirus/efeitos dos fármacos , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Fluoruracila/química , Fluoruracila/farmacologia , Modelos Moleculares , Pandemias , Pneumonia Viral/virologia , Células Vero , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
19.
Int J Nanomedicine ; 15: 2765-2776, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425520

RESUMO

Purpose: Over the past decades, quantum dots (QDs) have shown the broad application in diverse fields, especially in intracellular probing and drug delivery, due to their high fluorescence intensity, long fluorescence lifetime, strong light-resistant bleaching ability, and strong light stability. Therefore, we explore a kind of therapeutic potential against cancer with fluorescent imaging. Methods: In the current study, a new type of QDs (QDs@L-Cys-TAEA-5-FUA) capped with L-cysteine (L-Cys) and tris(2-aminoethyl)amine (TAEA) ligands, and conjugated with 5-fluorouracil-1-acetic acid (5-FUA) has been synthesized. Ligands were characterized by electrospray ionization mass spectrometry and H-nuclear magnetic resonance (1H NMR) spectroscopy. The modified QDs were characterized by transmission electron microscopy, ultraviolet and visible spectrophotometry (UV-Vis), and fluorescence microscopy. And the biological activity of modified QDs was explored by using MTT assay with HeLa, SMMC-7721 HepG2, and QSG-7701 cells. The fluorescence imaging of modified QDs was obtained by fluorescence microscope. Results: The modified QDs are of controllable sizes in the range of 4-5 nm and they possess strong optical emission properties. UV-Vis and fluorescence spectra demonstrated that the L-Cys-TAEA-5-FUA was successfully incorporated into QD nanoparticles. The MTT results demonstrated that L-Cys-TAEA-5-FUA modified QDs could efficiently inhibit the proliferation of cancer cells as compared to the normal cells, illustrating their antitumor efficacy. The mechanistic studies revealed that the effective internalization of modified QDs inside cancer cells could inhibit their proliferation, through excessive production of intracellular reactive oxygen species, leading to apoptosis process. Conclusion: The present study suggests that modified QDs can enter cells efficiently and could be employed as therapeutic agents for the treatment of various types of cancers with fluorescent imaging.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Fluoruracila/farmacologia , Pontos Quânticos/química , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cisteína/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Etilenodiaminas/química , Fluoruracila/administração & dosagem , Fluoruracila/química , Células HeLa , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Pontos Quânticos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Espectrofotometria Ultravioleta
20.
Int J Nanomedicine ; 15: 2777-2787, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368054

RESUMO

Background: Owing to its combined effects, the co-delivery of different therapeutics is a promising option for the treatment of cancer. In the present study, tumor-targeting poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) nanoparticles were developed for the transportation of two molecules, namely chemotherapeutic drug 5-fluorouracil (5Fu) and radionuclide iodine-131 (131I), in a single platform. Methods: The obtained nanoparticles (Cetuximab [Cet]-PEG-PLA-5Fu-131I) were spherical (diameter approximately 110 nm) and pH-sensitive. The targeting effect of nanoparticles via Cet was confirmed in colorectal cancer cells using a fluorescent assay. The combined effects of Cet-PEG-PLA-5Fu-131I on cell viability and apoptosis were evaluated in colorectal cancer cells by Cell Counting Kit-8 and flow cytometry assays. Results: Blank nanoparticles (Cet-PEG-PLA) showed good biocompatibility, and Cet-PEG-PLA-5Fu-131I nanoparticles were the most effective in terms of inhibition of cell viability and induction of apoptosis compared with monotherapy using Cet-PEG-PLA-5Fu or Cet-PEG-PLA-131I. In the xenograft mouse model, compared with using Cet-PEG-PLA-5Fu or Cet-PEG-PLA-131I alone, Cet-PEG-PLA-5Fu-131I nanoparticles exhibited prolonged circulation in the blood and accumulation in the tumor, thus resulting in enhanced antitumor efficacy. Additionally, combined radio-chemotherapy with Cet-PEG-PLA-5Fu-131I nanoparticles was associated with smaller tumor sizes than monotherapy, revealing the superior antitumor effects of Cet-PEG-PLA-5Fu-131I nanoparticles. These effects were further evidenced by histological and immunohistochemical analyses. Conclusion: The multifunctional Cet-PEG-PLA-5Fu-131I nanoparticles are promising candidates for the co-delivery of 5Fu-mediated chemotherapy and 131I-mediated radiotherapy.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/administração & dosagem , Nanopartículas Multifuncionais/química , Animais , Antimetabólitos Antineoplásicos/farmacologia , Circulação Sanguínea , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/química , Neoplasias Colorretais/patologia , Sistemas de Liberação de Medicamentos/métodos , Fluoruracila/farmacologia , Humanos , Radioisótopos do Iodo/química , Radioisótopos do Iodo/farmacocinética , Camundongos Endogâmicos BALB C , Nanopartículas Multifuncionais/uso terapêutico , Polietilenoglicóis , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA