RESUMEN
High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.
Asunto(s)
Enfermedades Gastrointestinales/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Intestinos/efectos de los fármacos , Niacinamida/farmacología , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Sirtuina 1/antagonistas & inhibidores , Acetilación , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/patología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de la radiación , Intestinos/patología , Intestinos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Organoides , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Emerging evidence suggests a potential relationship between gut microbiota and the host response to chemotherapeutic drugs including 5-fluorouracil (5-Fu). Fusobacterium nucleatum (Fn) has been linked to the initiation and progression of colorectal cancer (CRC). Unfortunately, little was known about the relationship between Fn infection and chemotherapeutic efficacy. Here, we investigate the potential relationship between Fn infection and chemotherapeutic efficacy of 5-Fu in CRC. METHODS: Differentially expressed genes of CRC cell lines induced by Fn infection were analyzed based on a whole genome microarray analysis Then, we explored the relationship between upregulation of BIRC3 induced by Fn infection and chemoresistance to 5-Fu in vitro and in vivo. Furthermore, we dissected the mechanisms involved in Fn-induced BIRC3 expression. Finally, we investigated the clinical relevance of Fn infection, BIRC3 protein expression and chemoresistance to 5-Fu treatment in CRC patients. RESULTS: BIRC3 was the most upregulated gene induced by Fn infection via the TLR4/NF-κB pathway in CRC cells; Fn infection reduced the chemosensitivity of CRC cells to 5-Fu through upregulation of BIRC3 in vitro and in vivo. High Fn abundance correlated with chemoresistance in advanced CRC patients who received standard 5-Fu-based adjuvant chemotherapy after radical surgery. CONCLUSIONS: Our evidence suggests that Fn and BIRC3 may serve as promising therapeutic targets for reducing chemoresistance to 5-Fu treatment in advanced CRC.
Asunto(s)
Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Neoplasias Colorrectales/etiología , Resistencia a Antineoplásicos , Fluorouracilo/farmacología , Fusobacterium nucleatum/fisiología , Microbioma Gastrointestinal , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Adulto , Anciano , Animales , Apoptosis/efectos de los fármacos , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , ARN Interferente Pequeño/genética , Receptor Toll-Like 4/metabolismoRESUMEN
BACKGROUND: HER2 is a well-established therapeutic target in breast and gastric cancers, while the role of HER2 in colorectal cancer is unclear, and no studies have explored the impact of HER2 on the outcome of stage II colorectal cancer patients treated with 5-fluorouracial based adjuvant chemotherapy. METHODS: We analyzed HER2 mRNA expression of 206 patients in GSE39582 dataset and explored the impact of HER2 expression on benefit from adjuvant chemotherapy for stage II colon cancer patients. We further validated the finding by retrospectively analyzing HER2 detection of immunohistochemistry in a cohort of 282 patients in Fudan University Shanghai Cancer Center (FUSCC). RESULTS: In GSE39582 dataset, chemo-treated HER2-high patients had a better overall survival (OS) and relapse-free survival (RFS) versus chemo-naïve HER2-high patients (5-year OS: 100% vs 69.5%, 5-year RFS: 100% and vs 64%, Pâ¯=â¯0.027 and 0.025, respectively). On the contrary, chemo-treated HER2-low patients had a worse RFS compared with chemo-naïve HER2-low patients (5-year RFS: 65.6% vs 82.1%, Pâ¯=â¯0.022). In FUSCC cohort, chemo-treated HER2-positive patients exhibited better OS vs chemo-naïve HER2-positive patients (5-year OS: 100% vs 73.8%, Pâ¯<â¯0.001), and showed marginal evidence of a lower probability of recurrence (5-year RFS: 74.4% vs 58.7%, Pâ¯=â¯0.072). After stratifying by mismatch repair (MMR) status, the results only kept consistency in patients with pMMR status. CONCLUSIONS: HER2-positve patients with stage II colorectal cancer can benefit from 5-fluorouracial based adjuvant chemotherapy, especially for patients with pMMR status.
Asunto(s)
Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Receptor ErbB-2/metabolismo , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN , Femenino , Fluorouracilo/uso terapéutico , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Peritoneal metastasis of colorectal cancer is one of the most incident and fateful diseases among relapse cases. It shows a certain resistance to systemic chemotherapy. The perfusion system in clinic is complex and hard to be used in fundamental researches. This study aims at evaluating the effect of an improved hyperthermic intraperitoneal chemotherapy with Raltitrexed used in tumor-bearing mice with peritoneal metastatic colorectal carcinoma. The results showed that no severe adverse effect was observed. All control animals developed extensive peritoneal and mesenteric metastatic nodes. Tumor sites in the treatment groups were reduced significantly. The administration dose of Raltitrexed influenced concentration in systemic blood and peritoneal tissues. Temperature promoted the intracellular absorption of Raltitrexed significantly. Our findings reveal that hyperthermic intraperitoneal chemotherapy is an efficient therapy in treating peritoneal metastatic carcinoma in nude mice. It can effectively reduce the extension of carcinoma cells from macro and micro examination. The combination of hyperthermia and Raltitrexed resulted in an improved therapeutic effect on animal models.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Hipertermia Inducida , Neoplasias Peritoneales/tratamiento farmacológico , Quinazolinas/administración & dosificación , Tiofenos/administración & dosificación , Absorción Fisiológica , Animales , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma/patología , Carcinoma/secundario , Carcinoma/terapia , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Terapia Combinada/efectos adversos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Semivida , Calor , Humanos , Hipertermia Inducida/efectos adversos , Infusiones Parenterales , Masculino , Ratones Desnudos , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/terapia , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Quinazolinas/uso terapéutico , Distribución Aleatoria , Tiofenos/efectos adversos , Tiofenos/farmacocinética , Tiofenos/uso terapéutico , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Lymph node (LN) status is a major indicator of stage and survival of lung cancer patients. LN dissection is a primary option for lung cancer LN metastasis; however, this strategy elicits adverse effects and great trauma. Therefore, developing a minimally invasive technique to cure LN metastasis of lung cancer is desired. In this study, multiwalled carbon nanotubes (MWNTs) coated with manganese oxide (MnO) and polyethylene glycol (PEG) (namely MWNTs-MnO-PEG) was employed as a lymphatic theranostic agent to diagnose and treat metastatic LNs. After single local injection and lymph drainage were performed, regional LNs were clearly mapped by T1-weighted magnetic resonance (MR) of MnO and dark dye imaging of MWNTs. Meanwhile, metastatic LNs could be simultaneously ablated by near-infrared (NIR) irradiation under the guidance of dual-modality mapping. The excellent result was obtained in mice bearing LNs metastasis models, showing that MWNTs-MnO-PEG as a multifunctional theranostic agent was competent for dual-modality mapping guided photothermal therapy of metastatic LNs.
Asunto(s)
Materiales Biocompatibles Revestidos , Hipotermia Inducida , Neoplasias Pulmonares/terapia , Compuestos de Manganeso , Nanotubos de Carbono/química , Neoplasias Experimentales/terapia , Óxidos , Fototerapia , Animales , Línea Celular Tumoral , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Ratones , Ratones Desnudos , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Óxidos/química , Óxidos/farmacologíaRESUMEN
PURPOSE: Metabolic phenotyping has provided important biomarker findings, which, unfortunately, are rarely replicated across different sample sets due to the variations from different analytical and clinical protocols used in the studies. To date, very few metabolic hallmarks in a given cancer type have been confirmed and validated by use of a metabolomic approach and other clinical modalities. Here, we report a metabolomics study to identify potential metabolite biomarkers of colorectal cancer with potential theranostic value. EXPERIMENTAL DESIGN: Gas chromatography-time-of-flight mass spectrometry (GC-TOFMS)-based metabolomics was used to analyze 376 surgical specimens, which were collected from four independent cohorts of patients with colorectal cancer at three hospitals located in China and City of Hope Comprehensive Cancer Center in the United States. Differential metabolites were identified and evaluated as potential prognostic markers. A targeted transcriptomic analysis of 29 colorectal cancer and 27 adjacent nontumor tissues was applied to analyze the gene expression levels for key enzymes associated with these shared metabolites. RESULTS: A panel of 15 significantly altered metabolites was identified, which demonstrates the ability to predict the rate of recurrence and survival for patients after surgery and chemotherapy. The targeted transcriptomic analysis suggests that the differential expression of these metabolites is due to robust metabolic adaptations in cancer cells to increased oxidative stress as well as demand for energy, and macromolecular substrates for cell growth and proliferation. CONCLUSIONS: These patients with colorectal cancer, despite their varied genetic background, mutations, pathologic stages, and geographic locations, shared a metabolic signature that is of great prognostic and therapeutic potential.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Perfilación de la Expresión Génica/métodos , Metabolómica/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/terapia , Metabolismo Energético/genética , Femenino , Estudios de Seguimiento , Cromatografía de Gases y Espectrometría de Masas , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Metaboloma/genética , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del TratamientoRESUMEN
To better understand the impact of undernutrition, nutritional risk, and nutritional treatment on the clinical outcomes of hospitalized cancer patients in China, the authors conducted a multicenter, cross-sectional study with 2248 cancer patients from 20 hospitals from January to June 2010. The authors defined 19.7% and 26.8% patients as undernourished at baseline and reassessment, respectively. Patients with gastrointestinal malignancies had a higher rate of undernutrition than other patients. The nutritional risk rate was 24.6% and 40.2% at baseline and reassessment, respectively. For patients with nutritional risk, the relative risk (RR) of adverse events (AEs) significantly increased with and without nutritional treatment. In comparison with the nonnutritional treatment subgroup, patients who received enteral nutrition (EN) or total parenteral nutrition (TPN) significantly reduced the RR of AE development. The RR of AEs for EN and TPN were 0.08 (95% CI: 0.01-0.62) and 0.56 (95% CI: 0.33-0.96), respectively. Separated nutrient infusion increased the risk of AEs. The authors concluded that undernutrition and nutritional risk are general problems that impact the outcomes of hospitalized cancer patients in China. Higher NRS2002 scores are related to AE risk but not weight loss. In nutritional treatment, EN and TPN can significantly reduce the risk of AEs.