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1.
Anticancer Res ; 40(2): 837-840, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014926

RESUMEN

BACKGROUND/AIM: The study aimed to test the potential for increasing the antiproliferative activity of 5-fluorouracil against breast cancer cells of various molecular subtypes by vitamin D receptor (VDR) agonists, calcitriol and tacalcitol, used at a low concentration of 10 nM. MATERIALS AND METHODS: Calcitriol and tacalcitol were used to increase the antiproliferative effect of 5-fluorouracil against the following human breast cancer cell lines: MCF-7, T47D, BT-474 (luminal); JIMT-1, SKBR-3 (HER2-enriched); MDA-MB-231 (triple-negative/basal-B), and non-malignant MCF-10A breast epithelial cells. RESULTS: Both calcitriol and tacalcitol significantly increased the sensitivity of MCF-7 and BT-474 cells to the antiproliferative effect of 5-fluorouracil, while no increase in the sensitivity of MDA-MB-231 cells to 5-fluorouracil treatment was observed. CONCLUSION: The VDR agonist used at the relatively low concentration of 10 nM may increase the sensitivity of breast cancer cells, at least of the luminal subtype, to the antiproliferative effect of 5-fluorouracil.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Fluorouracilo/uso terapéutico , Receptores de Calcitriol/agonistas , Línea Celular Tumoral , Fluorouracilo/farmacología , Humanos , Células MCF-7/metabolismo
2.
Anticancer Res ; 40(2): 915-921, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014935

RESUMEN

BACKGROUND/AIM: This study aimed was to clarify the impact of pegfilgrastim (PEG) 3.6 mg primary prophylaxis of febrile neutropenia (FN) on the average relative dose intensity (ARDI) of neoadjuvant/adjuvant FEC-100 for breast cancer. MATERIALS AND METHODS: This retrospective, single-centre cohort study including 296 patients who received FEC-100 compared PEG and non-PEG groups. The PEG group received PEG 3.6 mg as a single subcutaneous injection in each study cycle. The primary endpoint was the ARDI of FEC-100. The secondary endpoints were patient percentage of ARDI≥85%, factors associated with ARDI≥85%, and reasons for reduced ARDI. RESULTS: The PEG group showed significantly higher mean ARDI (95.6% versus 90.7%, p<0.001) and patient percentage of ARDI≥85% (93.0% versus 79.9%, p=0.001). PEG was significantly associated with ARDI≥85% (p=0.009). Neutropenia and FN, the main reasons for reduced ARDI, were significantly lower in the PEG group (p<0.05). CONCLUSION: Primary PEG 3.6 mg prophylaxis increased the ARDI of FEC-100.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Filgrastim/uso terapéutico , Terapia Neoadyuvante/métodos , Polietilenglicoles/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Estudios de Cohortes , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Epirrubicina/farmacología , Epirrubicina/uso terapéutico , Femenino , Filgrastim/farmacología , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Polietilenglicoles/farmacología , Estudios Retrospectivos
3.
Cancer Sci ; 111(3): 962-973, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31960523

RESUMEN

Tumors consist of heterogeneous cell populations that contain cancer cell subpopulations with anticancer drug-resistant properties called "persister" cells. While this early-phase drug tolerance is known to be related to the stem cell-like characteristic of persister cells, how the stem cell-related pathways contribute to drug resistance has remained elusive. Here, we conducted a single-cell analysis based on the stem cell lineage-related and gastric cell lineage-related gene expression in patient-derived gastric cancer cell models. The analyses revealed that 5-fluorouracil (5-FU) induces a dynamic change in the cell heterogeneity. In particular, cells highly expressing stem cell-related genes were enriched in the residual cancer cells after 5-FU treatment. Subsequent functional screening identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a specific marker and potential therapeutic target of persister cells. ALDH1A3 was selectively overexpressed among the ALDH isozymes after treatment with 5-FU or SN38, a DNA topoisomerase I inhibitor. Attenuation of ALDH1A3 expression by RNA interference significantly suppressed cell proliferation, reduced the number of persister cells after anticancer drug treatment and interfered with tumor growth in a mouse xenograft model. Mechanistically, ALDH1A3 depletion affected gene expression of the mammalian target of rapamycin (mTOR) cell survival pathway, which coincided with a decrease in the activating phosphorylation of S6 kinase. Temsirolimus, an mTOR inhibitor, reduced the number of 5FU-tolerant persister cells. High ALDH1A3 expression correlated with worse prognosis of gastric cancer patients. These observations indicate that the ALDH1A3-mTOR axis could be a novel therapeutic target to eradicate drug-tolerant gastric cancer cells.


Asunto(s)
Aldehído Oxidorreductasas/genética , Antineoplásicos/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Serina-Treonina Quinasas TOR/genética , Animales , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Células Madre Neoplásicas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
4.
Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892553

RESUMEN

BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.


Asunto(s)
Carcinoma de Células Escamosas/genética , Cisplatino/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de la Boca/genética , Oncogenes , Factores de Transcripción/genética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Fluorouracilo/farmacología , Humanos
5.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892565

RESUMEN

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Fluorouracilo/farmacología , Xenoinjertos , Humanos , Receptores de Hialuranos/genética , Ratones
6.
DNA Cell Biol ; 39(1): 69-77, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31702387

RESUMEN

Chemoresistance is one of the major obstacles for cancer therapy. Abnormal expression of long noncoding RNAs (lncRNAs) was broadly implicated in chemoresistance of multiple cancers. This study was aimed to investigate the function of urothelial cancer associated 1 (UCA1) in multidrug resistance of retinoblastoma and its potential molecular mechanism. In this study, we observed that UCA1 was significantly upregulated in chemoresistant retinoblastoma tissues and multidrug resistant retinoblastoma cell lines and predicted an unfavorable overall survival. Functionally, knockdown of UCA1 remarkably inhibited proliferation and sensitized retinoblastoma cells to multiple chemotherapy drugs, including vincristine (VCR), carboplatin (CBP), cisplatin (DDP), VP-16 (etoposide), and 5-fluorouracil (5-Fu). Mechanistic studies demonstrated that UCA1 functioned as a miRNA sponge to increase stathmin 1 (STMN1) expression through sponging miR-513a-5p. In addition, silence of miR-513a-5p or STMN1 overexpression could partly reverse UCA1 knockdown-induced inhibitory effects on proliferation and multidrug resistance of retinoblastoma cells. Overall, this study is the first to demonstrate that UCA1 plays a critical role in retinoblastoma chemoresistance, and UCA1 may serve as a potential diagnostic biomarker and therapeutic target of retinoblastoma.


Asunto(s)
Proliferación Celular/genética , Resistencia a Múltiples Medicamentos/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Retinoblastoma/genética , Antineoplásicos/farmacología , Carboplatino/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Etopósido/farmacología , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Retinoblastoma/tratamiento farmacológico , Retinoblastoma/patología , Vincristina/farmacología
7.
Cancer Sci ; 111(2): 658-666, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31823471

RESUMEN

Metabolic reprogramming, including the Warburg effect, is a hallmark of cancer. Indeed, the diversity of cancer metabolism leads to cancer heterogeneity, but accurate assessment of metabolic properties in tumors has not yet been undertaken. Here, we performed absolute quantification of the expression levels of 113 proteins related to carbohydrate metabolism and antioxidant pathways, in stage III colorectal cancer surgical specimens from 70 patients. The Warburg effect appeared in absolute protein levels between tumor and normal mucosa specimens demonstrated. Notably, the levels of proteins associated with the tricarboxylic citric acid cycle were remarkably reduced in the malignant tumors which had relapsed after surgery and treatment with 5-fluorouracil-based adjuvant therapy. In addition, the efficacy of 5-fluorouracil also decreased in the cultured cancer cell lines with promotion of the Warburg effect. We further identified nine and eight important proteins, which are closely related to the Warburg effect, for relapse risk and 5-fluorouracil benefit, respectively, using a biomarker exploration procedure. These results provide us a clue for bridging between metabolic protein expression profiles and benefit from 5-fluorouracil adjuvant chemotherapy.


Asunto(s)
Antioxidantes/metabolismo , Metabolismo de los Hidratos de Carbono , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Adulto , Anciano , Quimioterapia Adyuvante , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
8.
Anticancer Res ; 39(12): 6463-6470, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810910

RESUMEN

BACKGROUND/AIM: The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model. MATERIALS AND METHODS: A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week. RESULTS: All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group. CONCLUSION: These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Trabectedina/administración & dosificación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Peso Corporal/efectos de los fármacos , Camptotecina/administración & dosificación , Camptotecina/farmacología , Neoplasias Colorrectales/metabolismo , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Leucovorina/administración & dosificación , Leucovorina/farmacología , Ratones , Ratones Desnudos , Ratones Transgénicos , Distribución Aleatoria , Trabectedina/farmacología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Anticancer Res ; 39(12): 6555-6565, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810921

RESUMEN

BACKGROUND/AIM: Honokiol is a biphenolic component of the bark of Magnolia, and has been shown to exert several activities, including anti-depressant, anti-emetic, anti-oxidative, anti-thrombotic, anti-angiogenesis, anti-anxiolytic, anti-inflammatory and anti-tumor effects. MATERIALS AND METHODS: The anti-tumor activities of honokiol and its synergistic effect with 5-fluorouracil (5-FU) in human urothelial cell carcinoma (UCC) cells were investigated. RESULTS: Honokiol significantly suppressed the proliferation of UCC cells in a dose- and time-dependent manner. Moreover, honokiol inhibited the tumorigenesis of UCC cells in vitro. In addition, honokiol induced cell cycle arrest at G0/G1 phase and caused apoptosis of UCC cells through the intrinsic pathway. Importantly, we demonstrated that honokiol potentiated the cytotoxic effect of 5-FU, and displayed a synergistic effect with 5-FU in UCC cells. CONCLUSION: Honokiol causes growth inhibition, tumorigenesis suppression, cell cycle arrest, apoptosis, and importantly has a synergistic effect with 5-FU in human UCC cells. Therefore, this agent displays a therapeutic potential for treating human UCC.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Compuestos de Bifenilo/farmacología , Fluorouracilo/farmacología , Lignanos/farmacología , Neoplasias de la Vejiga Urinaria/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico
10.
Anticancer Res ; 39(12): 6673-6684, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810932

RESUMEN

BACKGROUND/AIM: The aim of the study was to evaluate the antitumor potential and combination effects of chemotherapeutic drugs. MATERIALS AND METHODS: The cytotoxicity of 20 drip-type classical and molecular-targeted anticancer drugs was examined against 4 human oral squamous cell carcinoma cell lines and 5 human oral normal mesenchymal and epithelial cells. Cell cycle progression was monitored by a cell sorter. Combination effect was evaluated by combination index. RESULTS: Most of the classical anticancer drugs showed much higher antitumor activity than molecular-targeted drugs, except bortezomib. Among 12 classical anticancer drugs, taxanes and gemsitabine showed the highest tumor-specificity (TS) and potency-selectivity expression (PSE) values, whereas platinum analogs showed the least TS value. Combination of two classical or a classical and a molecular-targeted drug showed mostly additive or antagonistic effect. 5-FU and cisplatin did not produce a subG1 population, but induced G2/M or G1/S arrest, regardless of the addition of cetuximab. Cetuximab, nibolumab and bortezomib showed potent keratinocyte toxicity. CONCLUSION: The present TS monitoring system may provide useful information for building up the treatment regimens of anticancer drugs.


Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Células Epiteliales/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias de la Boca/tratamiento farmacológico , Bortezomib/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cetuximab/farmacología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/efectos de los fármacos , Fluorouracilo/farmacología , Hormesis , Humanos , Técnicas In Vitro , Queratinocitos/efectos de los fármacos , Mucosa Bucal/citología , Nivolumab/farmacología , Compuestos de Platino/farmacología , Taxoides/farmacología
11.
Int J Nanomedicine ; 14: 9259-9273, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31819428

RESUMEN

Purpose: The main goal of this study is to evaluate the impact of physical incorporation of polyethylene glycol (PEG) into 5-fluorouracil (5-FU)-loaded polymeric nanoparticles (NPs). Methods: The 5-FU-loaded NPs were prepared utilizing a simple double emulsion method using polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA) with or without PEG 6000. The surface charge, particle size, and shape of NPs were evaluated by standard procedures. Both Fourier Transform Infrared Spectroscopy and X-ray diffraction spectra of the 5-FU loaded NPs were compared against the pure 5-FU. The in vitro release profile of 5-FU from the NPs was monitored by the dialysis tubing method. Cell death and apoptosis induction in response to 5-FU NP exposure were measured by MTT and Annexin-V/7-amino-actinomycin D (7-AAD) assays, respectively, in Daoy, HepG2, and HT-29 cancer cell lines. Results: The 5-FU loaded NPs were found to be spherical in shape with size ranging between 176±6.7 and 253.9±8.6 nm. The zeta potential varied between -7.13± 0.13 and -27.06±3.18 mV, and the entrapment efficiency was between 31.96% and 74.09%. The in vitro release of the drug followed a two-phase mode characterized by rapid release in the first 8 hrs followed by a period of slow release up to 72 hrs with composition-based variable extents. Cells exposed to NPs demonstrated a significant cell death which correlated with the ratio of PEG in the formulations in Daoy and HepG2 cells but not in HT-29 cells. Formulations (F1-F3) significantly induced early apoptosis in HT-29 cell lines. Conclusion: The physical PEGylation significantly enhanced the entrapment and loading efficiencies of 5-FU into NPs formulated with PLGA and PCL. It also fostered the in vitro cytotoxicity of 5-FU-loaded NPs in both Daoy and HepG2 cells. Induction of early apoptosis was confirmed for some of the formulations.


Asunto(s)
Fluorouracilo/farmacología , Nanopartículas/química , Poliésteres/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Liberación de Fármacos , Fluorouracilo/química , Células HT29 , Humanos , Nanopartículas/ultraestructura , Tamaño de la Partícula , Polietilenglicoles/química , Electricidad Estática , Difracción de Rayos X
12.
Nat Commun ; 10(1): 5349, 2019 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-31836706

RESUMEN

Increased levels and non-telomeric roles have been reported for shelterin proteins, including RAP1 in cancers. Herein using Rap1 null mice, we provide the genetic evidence that mammalian Rap1 plays a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 is independent of its association with the telomere or with its known partner TRF2. We show that RAP1 interacts with many members of the DNA damage response (DDR) pathway. RAP1 depleted cells show reduced interaction between XRCC4/DNA Ligase IV and DNA-PK, and are impaired in DNA Ligase IV recruitment to damaged chromatin for efficient repair. Consistent with its role in DNA damage repair, RAP1 loss decreases double-strand break repair via NHEJ in vivo, and consequently reduces B cell class switch recombination. Finally, we discover that RAP1 levels are predictive of the success of chemotherapy in breast and colon cancer.


Asunto(s)
Antineoplásicos/farmacología , Carcinogénesis/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteínas de Unión a Telómeros/metabolismo , Proteínas de Unión al GTP rap1/metabolismo , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Daño del ADN , ADN Ligasa (ATP)/metabolismo , Reparación del ADN/efectos de los fármacos , Reparación del ADN/efectos de la radiación , Proteína Quinasa Activada por ADN/metabolismo , Fluorouracilo/farmacología , Rayos gamma , Inestabilidad Genómica/efectos de los fármacos , Inestabilidad Genómica/efectos de la radiación , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de la radiación , Humanos , Ratones Noqueados , Mutágenos/toxicidad , Unión Proteica/efectos de los fármacos , Unión Proteica/efectos de la radiación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Análisis de Supervivencia
13.
Int J Nanomedicine ; 14: 6661-6678, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31695362

RESUMEN

Background: Cancer treatments are being continually developed. Increasingly more effective and better-targeted treatments are available. As treatment has developed, the outcomes have improved. Purpose: In this work, polyethylene glycol (PEG), layered double hydroxide (LDH) and 5-fluorouracil (5-FU) were used as a stabilizing agent, a carrier and an anticancer active agent, respectively. Characterization and methods: Magnetite nanoparticles (Fe3O4) coated with polyethylene glycol (PEG) and co-coated with 5-fluorouracil/Mg/Al- or Zn/Al-layered double hydroxide were synthesized by co-precipitation technique. Structural, magnetic properties, particle shape, particle size and drug loading percentage of the magnetic nanoparticles were investigated by XRD, TGA, FTIR, DLS, FESEM, TEM, VSM, UV-vis spectroscopy and HPLC techniques. Results: XRD, TGA and FTIR studies confirmed the formation of Fe3O4 phase and the presence of iron oxide nanoparticles, polyethylene glycol, LDH and the drug for all the synthesized samples. The size of the nanoparticles co-coated with Mg/Al-LDH is about 27 nm compared to 40 nm when they were co-coated with Zn/Al-LDH, with both showings near uniform spherical shape. The iron oxide nanoparticles retain their superparamagnetic property when they were coated with polyethylene glycol, polyethylene glycol co-coated with Mg/Al-LDH and polyethylene glycol co-coated with Zn/Al-LDH with magnetic saturation value of 56, 40 and 27 emu/g, respectively. The cytotoxicity study reveals that the anticancer nanodelivery system has better anticancer activity than the free drug, 5-FU against liver cancer HepG2 cells and at the same time, it was found to be less toxic to the normal fibroblast 3T3 cells. Conclusion: These are unique core-shell nanoparticles synthesized with the presence of multiple functionalities are hoped can be used as a multifunctional nanocarrier with the capability of targeted delivery using an external magnetic field and can also be exploited as hypothermia for cancer cells in addition to the chemotherapy property.


Asunto(s)
Fluorouracilo/farmacología , Hidróxidos/química , Fenómenos Magnéticos , Polietilenglicoles/química , Nanomedicina Teranóstica , Células 3T3 , Animales , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Dispersión Dinámica de Luz , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/ultraestructura , Ratones , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura Ambiental , Difracción de Rayos X
14.
Anticancer Res ; 39(11): 6041-6047, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31704830

RESUMEN

BACKGROUND/AIM: We have previously reported that alternate-day S-1 had comparable effects and milder adverse events than the respective consecutive-day regimen in head and neck cancer (HNC) patients. The aim of this study was to investigate the anticancer effects of both regimens and underlying mechanisms in vitro. MATERIALS AND METHODS: Two head and neck squamous cell carcinoma (HNSCC) cell lines were treated with 5-FU given on an alternate-day or consecutive-day schedule. The relative inhibition (RI) of tumor growth was calculated. Cell cycle distributions and cyclin expression following 5-FU treatment were analyzed. RESULTS: The RI of both regimens was almost identical. The percentage of cells in S phase was significantly increased in the alternate-day group compared to the consecutive-day group (p<0.001). CONCLUSION: The cytotoxic effect of alternate-day was equivalent to that of consecutive-day. S-phase arrest was more prominently observed with the alternate-day regimen, which may help maintain 5-FU sensitivity in head and neck cancer cells.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fluorouracilo/farmacología , Neoplasias de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Esquema de Medicación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Técnicas In Vitro , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Células Tumorales Cultivadas
15.
Biochemistry (Mosc) ; 84(11): 1424-1432, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31760928

RESUMEN

A large body of evidence suggests that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), as well as expression and function of retinoid receptors, are pivotal features of tumor initiation, progression, and chemoresistance. This is also true for pancreatic ductal adenocarcinoma (PDAC), which represents a clinical challenge due to poor prognosis and increasing incidence. Understanding the above features of cancer cells could open new avenues for PDAC treatment strategies. The aim of this study was to investigate the relation between CSCs, EMT, and retinoid receptors in PDAC after treatment with the chemotherapeutic agents - gemcitabine and 5-fluorouracil. First, we demonstrated the difference in the expression levels of CSC and EMT markers and retinoid receptors in the untreated Mia PaCa-2 and Panc1 cells that also differed in the frequency of spontaneous apoptosis and distribution between the cell cycle phases. Chemotherapy reduced the number of cancer cells in the S phase. Gemcitabine and 5-fluorouracil modulated expression of CSC markers, E-cadherin, and RXRß in Panc1 but not in Mia PaCa-2 cells. We suggest that these effects could be attributed to the difference in the basal levels of expression of the investigated genes. The obtained data could be interesting in the context of future preclinical research.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptor beta X Retinoide/metabolismo , Apoptosis/efectos de los fármacos , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Fluorouracilo/farmacología , Humanos , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Receptor beta X Retinoide/genética , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos
16.
Nat Cell Biol ; 21(11): 1309-1320, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31685996

RESUMEN

With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing.


Asunto(s)
Envejecimiento/genética , Capilares/metabolismo , Células Madre Hematopoyéticas/metabolismo , Homeostasis/genética , Nicho de Células Madre/genética , Envejecimiento/metabolismo , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Capilares/citología , Capilares/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Rastreo Celular/métodos , Doxiciclina/farmacología , Fluorouracilo/farmacología , Regulación de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Histonas/genética , Histonas/metabolismo , Homeostasis/efectos de los fármacos , Proteína Jagged-2/genética , Proteína Jagged-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Agonistas Mieloablativos/farmacología , Nicho de Células Madre/efectos de los fármacos
17.
Biol Pharm Bull ; 42(10): 1733-1740, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31582661

RESUMEN

The aim of this study was to clarify the relationship between chemotherapy-induced mucositis and endogenous glucagon-like peptide-2 (GLP-2) dynamics in the small intestine following treatment with either methotrexate or 5-fluorouracil. Rats were injected intraperitoneally with a single dose of either 50 mg/kg methotrexate or 100 mg/kg 5-fluorouracil. At 24 and 72 h after drug administration, ileal tissues and plasma were used to investigate GLP-2 dynamics. Administration of methotrexate caused moderate but not significant intestinal injury within 72 h, while administration of 5-fluorouracil caused severe injury in a time-dependent manner. Methotrexate significantly increased proglucagon mRNA expression and the number of anti-GLP-2 antibody-positive cells in the ileal tissue at 24 h after administration. Methotrexate also significantly induced GLP-2 receptor, insulin-like growth factor-1 (IGF-1), and transforming growth factor-ß2 (TGF-ß2) mRNA expression in ileal tissue. In contrast, 5-fluorouracil significantly inhibited proglucagon, GLP-2 receptor, IGF-1, and TGF-ß2 mRNA expression as well as the number of anti-GLP-2 antibody-positive cells. Methotrexate slightly increased dipeptidyl peptidase IV (DPP-4) mRNA expression, whereas 5-fluorouracil significantly increased DPP-4 mRNA expression. These results suggest that potentiation of endogenous GLP-2 dynamics by methotrexate is associated with a mechanism that preserves gastrointestinal mucosal integrity at a moderate level.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Péptido 2 Similar al Glucagón/sangre , Intestino Delgado/efectos de los fármacos , Metotrexato/farmacología , Animales , Dipeptidil Peptidasa 4/genética , Fluorouracilo/farmacología , Receptor del Péptido 2 Similar al Glucagón/genética , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/patología , Masculino , Ratas Wistar
18.
Nat Med ; 25(10): 1607-1614, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31591597

RESUMEN

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.


Asunto(s)
Quimioradioterapia , Organoides/patología , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Animales , Fluorouracilo/farmacología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundario , Ratones , Metástasis de la Neoplasia , Organoides/efectos de los fármacos , Organoides/efectos de la radiación , Neoplasias del Recto/patología
19.
Cancer Sci ; 110(12): 3677-3688, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31646712

RESUMEN

5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that microRNA (miR)-338-5p was underexpressed in ESCC cells with acquired 5-FU chemoresistance. Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment. The effects were abolished by reexpression of Id-1. In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU. In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1. We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR-338-5p expression level was associated with poorer survival and poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy. In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.


Asunto(s)
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Proteína 1 Inhibidora de la Diferenciación/genética , MicroARNs/fisiología , Adulto , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular , Resistencia a Antineoplásicos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Fluorouracilo/farmacología , Humanos , Masculino , Ratones , MicroARNs/sangre , Persona de Mediana Edad , Invasividad Neoplásica
20.
Life Sci ; 239: 116888, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31639401

RESUMEN

5-Fluorouracil (5-FU)-induced intestinal mucositis (IM) is one of the most common oncological problem. It involves serious clinical consequences such as diarrhea, erythematous lesions of mucosa, and eventually development of ulcers accompanied by severe pain. The aim of the present study was to demonstrate the mucoprotective effects of Saikosaponin-A in 5-FU-induced intestinal mucositis in mice. Mucositis was induced in BALB/c mice by intraperitoneal injection of 5-FU (50 mg/kg/day) for three consecutive days and IM was assessed by both behavioral and histochemical analysis. While, Saikosaponin-A (1, 5, 10 mg/kg/day) was administered 1 h before 5-FU injection for consecutive seven days. Pre-treatment of Saikosaponin-A significantly ameliorated the severity of mucositis reflected as food intake, body weight loss, severity of diarrhea and mortality rate in a dose depended manner as compared to mice treated with 5-FU. Moreover, histopathological analysis furthered reinforced the mucoprotective potential of Saikosaponin-A against 5-FU-induced intestinal abnormalities referred as villus atrophy, mitotic crypt stem cells damage, inflammatory cells infiltration, vacuolization and edema. Furthermore, Saikosaponin-A administration strongly inhibited pro-inflammatory mediators (TNF-α, COX-2, IL-1ß and IL-6) and apoptotic markers (p-JNK, Casp-3). Saikosaponin-A pre-treatment significantly reduced the production of nitric oxide (NO) in intestinal tissue, inhibited acetic acid-induced Evans blue vascular permeability. The Siaikosaponin-A treatment markedly enhanced the anti-oxidants enzymes (Nrf2, HO-1, SOD, GSH, GST and Catalase), while decreased the oxidative stress markers i.e. Malonaldehde (MDA). Hence, these data suggest that Saikosaponin-A maybe a potential candidate for the treatment of chemotherapy-induced intestinal mucositis.


Asunto(s)
Mucosa Intestinal/efectos de los fármacos , Mucositis/tratamiento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacología , Animales , Antimetabolitos Antineoplásicos/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Citocinas , Diarrea/inducido químicamente , Modelos Animales de Enfermedad , Fluorouracilo/farmacología , Mucosa Intestinal/patología , Intestinos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Mucositis/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacología , Saponinas/metabolismo
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