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Radiotherapy leverages ionizing radiation to kill cancer cells through direct and indirect effects, and direct effects are considered to play an equal or greater role. Several photosensitizers have been developed to mimic the direct effects of radiotherapy, generating radical cations in DNA models, but none has been applied in cellular studies. Here, we design a radiomimetic photosensitizer, producing DNA radical cations in cells for the first time. To reduce adverse effects, several redox-inducible precursors are prepared as cancer cells have elevated levels of GSH and H2O2. These precursors respond to GSH or H2O2, releasing the active photosensitizer that captures DNA abasic (AP) sites and generates DNA radical cations upon photolysis, without disrupting the redox state of cells. DNA radical cations migrate freely and are eventually trapped by H2O and O2 to yield DNA lesions, thus triggering DNA damage response. Our study suggests that direct effects of radiotherapy suppress cancer cell proliferation mainly by inducing G2/M phase cell cycle arrest, rather than promoting apoptosis. Synergistic effects of the precursor and chemotherapeutic agents are also observed in combination phototherapy. Beyond highlighting an alternative strategy for phototherapy, this proof-of-concept study affords a facile cellular platform to study the direct effects of radiotherapy.
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SMARCA2 and SMARCA4 are the mutually exclusive catalytic subunits of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, and have recently been considered as attractive synthetic lethal targets for PROTAC-based cancer therapy. However, the potential off-tissue toxicity towards normal tissues remains a concern. Here, we optimize a GSH-inducible SMARCA2/4-based PROTAC precursor with selective antitumor activity towards lung cancer cells and negligible cytotoxicity towards normal cells in both in vitro and in vivo studies. The precursor is not bioactive or cytotoxic, but preferentially responds to endogenous GSH in GSH-rich lung cancer cells, releasing active PROTAC to degrade SMARCA2/4 via PROTAC-mediated proteasome pathway. Subsequent xenograft model study reveals that selective SMARCA2/4 degradation in lung tumors triggers DNA damage and apoptosis, which significantly inhibits lung cancer cell proliferation without obvious adverse events towards normal tissues. This study exemplifies the targeted degradation of SMARCA2/4 in lung cancer cells by the GSH-responsive PROTAC precursor, highlighting its potential as an encouraging cancer therapeutic strategy.
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ERα (estrogen receptor-α)-targeting PROTACs (PROteolysis TArgeting Chimeras) have emerged as a novel and promising modality for breast cancer therapeutics. However, ERα PROTACs-induced degradation in normal tissues raises concerns about potential off-tissue toxicity. Tumor microenvironment-responsive strategy provides potential for specific control of the PROTAC's on-target degradation activity. The glutathione (GSH) level has been reported to be significantly increased in tumor cells. Here, we designed a GSH-responsive ERα PROTAC, which is generated by conjugating an o-nitrobenzenesulfonyl group to the hydroxyl group of VHL-based ERα PROTAC through a nucleophilic substitution reaction. The o-nitrobenzenesulfonyl group as a protecting group blocks the bioactivity of ERα PROTAC (ER-P1), and that can be specifically recognized and removed by highly abundant GSH in cancer cells. Consequently, the GSH-responsive ERα PROTAC (GSH-ER-P1) exhibits significantly enhanced degradation of ERα in cancer cells compared to that in normal cells, leading to a remarkable inhibition of breast cancer cell proliferation and less toxic effects on normal cells. This study provides a potentially valuable strategy for breast cancer treatment using tumor microenvironment-responsive PROTACs.
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Neoplasias de la Mama , Receptor alfa de Estrógeno , Humanos , Femenino , Receptor alfa de Estrógeno/metabolismo , Neoplasias de la Mama/patología , Glutatión/metabolismo , Proteolisis , Microambiente TumoralRESUMEN
Two-dimensional materials are widely used in membrane separation, but the loose distribution and severe expansion between graphene oxide (GO) nanosheets limit its application. Here, we introduce a two-dimensional MOF material into the GO membrane to enhance its water permeance and separation performance. The MOF/GO composite membrane was prepared by vacuum filtration. The MOF and GO nanosheets were tightly stacked through the π-π effect, and the shortened transmission path and enhanced pore structure greatly improved the water permeance of the composite membrane. The MOF/GO membrane exhibited a high water permeance of 56.94 L m-2 h-1 bar-1. The rejection rates of methylene blue and was as methyl orange dyes were as high as 99.79% and 99.11%, respectively. At increased dye concentration, the rejection rate of methylene blue was still maintained greater than 99%. Dye rejection after 18 h of continuous operation remains above 90%. This work provides new ideas for improving membrane separation materials. The combination of two-dimensional heterogeneous materials can result in synergistic advantages for the development of composite membranes with high water permeance and high rejection rate.
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Colorantes , Azul de Metileno , Filtración , AguaRESUMEN
Elevated GSH and H2O2 in cancer cells is sometimes doubted due to their contrary reactivities. Here, we construct a dual-responsive fluorescent probe to confirm the conclusion, and employ this to exploit a redox-inducible DNA interstrand crosslink (ICL) precursor. It crosslinks DNA upon activation by GSH and H2O2, affording an alternative dual-responsive strategy.
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Reparación del ADN , Neoplasias , Peróxido de Hidrógeno , Daño del ADN , ADN/metabolismo , Oxidación-Reducción , Reactivos de Enlaces Cruzados , Neoplasias/genéticaRESUMEN
BRD4,as a transcriptional and epigenetic regulator to mediate cellular functions, plays an important role in cancer development.Targeting BRD4 with conventional inhibitors in cancer therapy requires high doses, which often leads to off-target and adverse effects. BRD4-targeted proteolysis-targeting chimeras (PROTACs) can catalytically degrade BRD4 utilizing the endogenous proteasome system, and exhibit promising anti-tumor activity. However, most of the developed PROTACs are non-cancer specific and relatively toxic towards normal cells, limiting their practical applications in cancer treatment. By taking advantage of higher glutathione (GSH) levels in cancer cells than that in normal cells, we developed several GSH-responsive PROTAC precursors 1a-c via the attachment of a GSH-trigger unit on the hydroxyl group of the VHL (von Hippel-Lindau) ligand for the recruitment of E3 ligase. Among the precursors, 1a can be efficiently activated by the innately higher concentrations of GSH in lung cancer cells (A549 and H1299) to release active PROTAC 1, degrading intracellular BRD4 and resulting in cytotoxicity, which is confirmed by mechanistic investigation. On the other hand, 1a cannot be efficiently triggered in normal lung cells (WI38 and HULEC-5a) containing lower levels of GSH, therefore reducing the adverse effects on normal cells. This work provides an alternative proof of concept approach for developing stimuli-responsive PROTAC precursors, and affords a novel insight to improve the selectivity and minimize the adverse effects of current PROTACs, hence enhancing their clinical potential.
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Neoplasias Pulmonares , Proteínas Nucleares , Quimera Dirigida a la Proteólisis , Humanos , Proteínas de Ciclo Celular , Proliferación Celular , Glutatión , Neoplasias Pulmonares/tratamiento farmacológico , Factores de TranscripciónRESUMEN
Proteolysis-targeting chimeras (PROTACs) provide a powerful technique to degrade targeted proteins utilizing the cellular ubiquitin-proteasome system. The major concern is the host toxicity resulting from their poor selectivity. Inducible PROTACs responding to exogenous stimulus, such as light, improve their specificity, but it is difficult for photo-activation in deep tissues. Herein, we develop H2 O2 -inducible PROTAC precursors 2/5, which can be activated by endogenous H2 O2 in cancer cells to release the active PROTACs 1/4 to effectively degrade targeted proteins. This results in the intended cytotoxicity towards cancer cells while targeted protein in normal cells remains almost unaffected. The higher Bromodomain-containing protein 4 (BRD4) degradation activity and cytotoxicity of 2 towards cancer cells is mainly due to the higher endogenous concentration of H2 O2 in cancer cells (A549 and H1299), characterized by H2 O2 -responsive fluorescence probe 3. Western blot assays and cytotoxicity experiments demonstrate that 2 degrades BRD4 more effectively and is more cytotoxic in H2 O2 -rich cancer cells than in H2 O2 -deficient normal cells. This method is also extended to estrogen receptor (ER)-PROTAC precursor 5, showing H2 O2 -dependent ER degradation ability. Thus, we establish a novel strategy to induce targeted protein degradation in a H2 O2 -dependent way, which has the potential to improve the selectivity of PROTACs.
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Peróxido de Hidrógeno , Neoplasias , Proteolisis , Peróxido de Hidrógeno/farmacología , Factores de Transcripción/metabolismo , Proteínas Nucleares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores de Estrógenos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias/tratamiento farmacológicoRESUMEN
Plant-associated bacteria play important regulatory roles in modulating plant hormone auxin levels, affecting the growth and yields of crops. A conserved auxin degradation (iad) operon was recently identified in the Variovorax genomes, which is responsible for root growth inhibition (RGI) reversion, promoting rhizosphere colonization and root growth. However, the molecular mechanism underlying auxin degradation by Variovorax remains unclear. Here, we systematically screened Variovorax iad operon products and identified 2 proteins, IadK2 and IadD, that directly associate with auxin indole-3-acetic acid (IAA). Further biochemical and structural studies revealed that IadK2 is a highly IAA-specific ATP-binding cassette (ABC) transporter solute-binding protein (SBP), likely involved in IAA uptake. IadD interacts with IadE to form a functional Rieske non-heme dioxygenase, which works in concert with a FMN-type reductase encoded by gene iadC to transform IAA into the biologically inactive 2-oxindole-3-acetic acid (oxIAA), representing a new bacterial pathway for IAA inactivation/degradation. Importantly, incorporation of a minimum set of iadC/D/E genes could enable IAA transformation by Escherichia coli, suggesting a promising strategy for repurposing the iad operon for IAA regulation. Together, our study identifies the key components and underlying mechanisms involved in IAA transformation by Variovorax and brings new insights into the bacterial turnover of plant hormones, which would provide the basis for potential applications in rhizosphere optimization and ecological agriculture.
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Ácidos Indolacéticos , Rizosfera , Ácidos Indolacéticos/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Plantas/metabolismo , Bacterias/metabolismo , Operón/genéticaRESUMEN
Arylboronic acid/esters and phenyl selenides-based quinone methide (QM) precursors were reported to induce DNA interstrand crosslink (ICL) formation upon reaction with the inherently high concentrations of H2O2 in cancer cells. However, some normal cells (such as macrophages) also contain high-levels of H2O2, which may interfere with precursors' selectivity. In order to enhance the spatiotemporal specificity by the photolysis, we developed photo- and H2O2- dual-responsive DNA ICL precursors 1-3, bearing a photo-responsive coumarin moiety and a H2O2 inducible phenyl selenide group. Precursors 1-3 are efficiently activated by photoirradiation and H2O2 to generate reactive QMs crosslinking DNA. Moreover, the reactivity of precursors can be modulated by the introduction of aromatic substituents (OMe, F), and the electron donating group (OMe) displays a more pronounced promoting effect on DNA ICL formation. A subsequent piperidine heat stability study confirmed that the formed QMs primarily alkylate dAs, dGs and dCs in DNA. Furthermore, 1-3 inhibit lung cancer cell (H1299) growth by inducing DNA damage and producing toxic reactive oxygen species (ROS) upon photolysis of released coumarin. This study illustrates the potent cytotoxicity achieved by novel photo/H2O2 dual-responsive QM precursors 1-3, affording a novel strategy for the development of inducible DNA interstrand cross-linkers.
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Reactivos de Enlaces Cruzados , Peróxido de Hidrógeno , Indolquinonas , Cumarinas/química , Daño del ADN/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Indolquinonas/farmacología , Fotólisis , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Humanos , Línea Celular TumoralRESUMEN
Biothiols play essential roles in balancing the redox state and modulating cellular functions. Fluorescent probes for monitoring/labelling biothiols often suffer from slow reaction rates, strong background fluorescence and cytotoxic byproduct release. Thus, developing facile and versatile probes to overcome the challenges is still in high demand. Here, we report four coumarin-maleimides as fast responding and fluorogenic probes to detect GSH or label peptides/proteins. The probes quantitatively and selectively react with GSH via Michael addition within 1-2 min, achieving an 11-196-fold increase in fluorescence quantum yield via blockage of the photoinduced electron transfer (PET) process. Optimized probe 4 is applied for the detection of GSH in vitro (A549 cells) and in vivo (zebrafish embryos). Taking advantage of the fast Michael addition between the maleimide moiety and the sulfhydryl group, we expand the application of our method for fluorescent labelling of peptides/proteins and for tracking their cellular uptake process. The labelling strategy works for both Cys-bearing and Cys-free proteins after the introduction of a sulfhydryl group using Traut's reagent. Fluorescence assay reveals that the TAT-peptide can efficiently enter cells, but H3 protein, part of nucleosomes, prefers to bind on the cell membrane by electrostatic interactions, shedding light on the cellular uptake activity of nucleosomes and affording a potential membrane staining strategy. Overall, our study illustrates the broad potential of coumarin-maleimide based dual-functional probes for GSH detection and versatile protein labelling in biochemical research.
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Nucleosomas , Pez Cebra , Animales , Compuestos de Sulfhidrilo , Péptidos , Glutatión , Colorantes Fluorescentes , Cumarinas , Cisteína , HomocisteínaRESUMEN
Abasic (AP) sites are one of the most common DNA lesions in cells. Aldehyde-reactive alkoxyamines capture AP sites and block the activity of APE1, the enzyme responsible for initiating their repair. Blocking the APE1 repair of AP sites leads to cell death, and it is an actively investigated approach for treating cancer. However, unselective AP site capture in different cells produces side effects and limits the application of alkoxyamines in chemotherapy. Herein we take advantage of the higher glutathione (GSH) concentration in cancer cells over normal cells to develop GSH-inducible agents that selectively kill cancer cells. 2,4-Dinitrobenzenesulfonamide caged coumarin-based alkoxyamines 1 and 2 are selectively revealed by GSH to release SO2 and fluorescent coumarin-based alkoxyamines 3 and 4 that trap AP sites in cells. GSH-directed AP site trapping and SO2 release result in selective cytotoxicity (defined as IC50WI38/IC50H1299) against H1299 lung cancer cells over normal WI38 lung cells, ranging from 1.8 to 2.8 for 1 and 2. The alkylating agent methylmethanesulfonate (MMS) promotes the formation of AP sites in cells and enhances the cytotoxicity of agent 1 in a dose-dependent way. Moreover, the comet assay and γH2AX assay suggest that AP adducts form a highly toxic DNA interstrand cross-link (ICL) upon photolysis, leading to further cell death. DNA flow cytometric analysis showed that 1 promoted cell apoptosis in the early stage and induced G2/M phase cell-cycle arrest. The 2,4-dinitrobenzenesulfonamide-caged alkoxyamines exhibited selective antitumor activity and photocytotoxicity in cancer cells, illuminating their potential as GSH-directed chemotherapeutic agents.
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Antineoplásicos , Reparación del ADN , ADN-(Sitio Apurínico o Apirimidínico) Liasa , Antineoplásicos/farmacología , Línea Celular Tumoral , ADN/metabolismo , Daño del ADN , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Glutatión , HumanosRESUMEN
DNA interstrand crosslinks (ICLs) are highly toxic DNA lesions, and induce cell death by blocking DNA strand separation. Most ICL agents aiming to kill cancer cells, also generate adverse side effects to normal cells. H2 O2 -inducible DNA ICL agents are highly selective for targeting cancer cells, as the concentration of H2 O2 is higher in cancer cells than normal cells. Previous studies have focused on arylboronate-based precursors, reacting with H2 O2 to generate reactive quinone methides (QMs) crosslinking DNA. Here we explore phenyl selenide-based precursors 1-3 as H2 O2 -inducible DNA ICL agents. The precursors 1-3 can be activated by H2 O2 to generate the good benzylic leaving group and promote production of reactive QMs to crosslink DNA. Moreover, the DNA cross-linking ability is enhanced by the introduction of substituents in the para-position of the phenolic hydroxyl group. From the substituents explored (H, OMe, F), the introduction of electron donating group (OMe) shows a pronounced elevating effect. Further mechanistic studies at the molecular and DNA levels confirm alkylation sites located mainly at dAs, dCs and dGs in DNA. Additionally, cellular experiments reveal that agents 1-3 exhibit higher cytotoxicity toward H1299 human lung cancer cells compared to clinically used drugs, by inducing cellular DNA damage, apoptosis and G0/G1 cell cycle arrest. This study provides a strategy to develop H2 O2 -inducible DNA interstrand cross-linkers.
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ADN , Peróxido de Hidrógeno , Alquilación , Reactivos de Enlaces Cruzados/farmacología , Daño del ADN , Reparación del ADN , HumanosRESUMEN
A combination of various risk factors results in the development of coronary heart disease. The earlier that one identifies and deals with reversible risk factors for coronary heart disease, the greater the chance of recovery. The main goal of this research is to learn whether risk variables are associated with greater extent of coronary artery disease in people with coronary heart disease. This article selects 290 patients who had had coronary angiography in our hospital from September 2018 to March 2019 using a retrospective research and analytic methodology. Coronary angiography split the patients into two groups: those with coronary heart disease and those without. To determine the correlation between risk factors and a score related to heart disease, computer-aided statistical analysis of data about the differences in those risk factors was performed. The results were analyzed using the Spearman correlation and partial correlation, and the relationship between risk factors and Gensini score was analyzed by multiple linear regression. For the analysis, binary logistic regression was used to calculate the correlation between the risk factors of coronary heart disease and the probability of developing coronary heart disease. The findings concluded that increased age, smoking, elevated hs-CRP, HbA1c, hypertension, diabetes, and hyperuricemia are all contributors to coronary heart disease. Coronary heart disease is an independent risk factor for this condition. Many of the factors that play a role in the long-term development of the severity of coronary artery disease, such as hypertension, diabetes, smoking, elevated hs-CRP, decreased HDL-C, raised LDL-C, and TG, are commonly found in men. hs-CRP is the primary risk factor for the degree of coronary artery stenosis and could contribute to the progression of the condition by playing a major role in creating more stenosis.
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Angiografía Coronaria/estadística & datos numéricos , Enfermedad Coronaria/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Biología Computacional , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad Coronaria/sangre , Enfermedad Coronaria/etiología , Estenosis Coronaria/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Diagnóstico por Computador/estadística & datos numéricos , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Modelos Lineales , Lípidos/sangre , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The prognostic role of preoperative fibrinogen in colorectal cancer (CRC) patients remains controversial. Therefore, we assessed the predictive value of preoperative fibrinogen and developed a tool for predicting the survival of CRC patients. METHODS: This retrospective study evaluated 1869 patients who underwent curative resection for CRC. Univariate and multivariate survival analyses were conducted to identify the factors correlated with overall survival (OS) and cancer-specific survival (CSS). Nomograms were developed as a graphical representation of the Cox proportional hazards regression models. The performance of the nomograms was assessed by Harrell's concordance index (c-index) and calibration plots. RESULTS: The preoperative fibrinogen levels were correlated with age, tumor differentiation, tumor location, pT category, and TNM stage. In the multivariate analysis, elevated fibrinogen level was independently correlated with worse OS and CSS (OS: hazard ratio [HR] = 0.777, 95% confidence interval [95% CI] = 0.630-0.958, P = 0.018; CSS: HR = 0.757, 95% CI = 0.605-0.947, P = 0.015). The nomograms could predict outcomes with a c-index for OS and CSS of 0.79 and 0.81, respectively. The nomograms also had a good calibration. CONCLUSION: Preoperative fibrinogen level was an independent marker of poor prognosis in patients with nonmetastatic CRC, and there was a threshold level for the use of fibrinogen as a prognostic factor. Furthermore, nomograms may help predict the individual risk of OS and CSS in patients treated for CRC.
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Gastric cancer (GC) is known as a top malignant type of tumors worldwide. Despite the recent decrease in mortality rates, the prognosis remains poor. Therefore, it is necessary to find novel biomarkers with early diagnostic value for GC. In this study, we present a large-scale proteomic analysis of 30 GC tissues and 30 matched healthy tissues using label-free global proteome profiling. Our results identified 537 differentially expressed proteins, including 280 upregulated and 257 downregulated proteins. The ingenuity pathway analysis (IPA) results indicated that the sirtuin signaling pathway was the most activated pathway in GC tissues whereas oxidative phosphorylation was the most inhibited. Moreover, the most activated molecular function was cellular movement, including tissue invasion by tumor cell lines. Based on IPA results, 15 hub proteins were screened. Using the receiver operating characteristic curve, most of hub proteins showed a high diagnostic power in distinguishing between tumors and healthy controls. A four-protein (ATP5B-ATP5O-NDUFB4-NDUFB8) diagnostic signature was built using a random forest model. The area under the curve (AUC) values of this model were 0.996 and 0.886 for the training and testing sets, respectively, suggesting that the four-protein signature has a high diagnostic power. This signature was further tested with independent datasets using plasma enzyme-linked immune sorbent assays, resulting in an AUC value of 0.778 for distinguishing GC tissues from healthy controls, and using immunohistochemical tissue microarray analysis, resulting in an AUC value of 0.805. In conclusion, this study identifies potential biomarkers and improves our understanding of the pathogenesis, providing novel therapeutic targets for GC.
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Neoplasias Gástricas , Biomarcadores de Tumor/genética , Detección Precoz del Cáncer , Humanos , Proteoma , Proteómica , Neoplasias Gástricas/diagnósticoRESUMEN
BACKGROUND: Colorectal neuroendocrine carcinoma (CRNEC) is a rare type of malignancy and is quite aggressive with dismal prognosis. Neither large-scale retrospective studies nor prospective studies have been performed to evaluate the prognostic value of adjuvant chemotherapy in patients with CRNEC. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, 318 elderly patients who were diagnosed with high-grade colorectal neuroendocrine tumors were included. The survival benefit was evaluated using a Cox proportional hazards model and propensity score-matched techniques. RESULTS: Among patients with stage I-III CRNEC, there was also no significant difference in cancer-specific survival (CSS) (P = 0.898) or overall survival (OS) (P = 0.539) between the 5-fluorouracil (5-FU) and the no chemotherapy groups. Meanwhile, the etoposide + platinum (EP) regimen showed no improved survival in patients with stage I-III CRNEC compared with the no chemotherapy group. For stage IV CRNEC, there was no significant difference between operation group and no operation group in CSS (P = 0.317) or OS (P = 0.385). Both 5-FU and EP regimens improved the CSS (for 5-FU, hazard ratio [HR] = 0.257, 95% confidence interval [CI] = 0.134-0.491, P < 0.001; for EP, HR = 0.348, 95% CI = 0.192-0.631, P = 0.001) and OS (for 5-FU, HR = 0.274, 95% CI = 0.149-0.502, P < 0.001; for EP, HR = 0.345, 95% CI = 0.194-0.612, P < 0.001) of patients in stage IV CRNEC. CONCLUSIONS: Our findings demonstrated that neither the 5-FU based nor EP chemotherapy regimens improved the CSS or OS for patients with stage I-III CRNEC. And for stage IV CRNEC, chemotherapy is an independent prognostic factor for CSS and OS, while operation could not improve the CSS or OS for patients with stage IV CRNEC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Neuroendocrino/terapia , Neoplasias Colorrectales/terapia , Programa de VERF/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Carcinoma Neuroendocrino/mortalidad , Carcinoma Neuroendocrino/patología , Quimioterapia Adyuvante/métodos , Colon/patología , Colon/cirugía , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Recto/patología , Recto/cirugía , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Increasing evidence suggests that metformin use is associated with a decreased risk of cancer. The traditional therapies for gastric cancer (GC) are gastrectomy and chemoradiotherapy; however, these therapies may cause certain adverse effects, which affect a patient's quality of life, and the overall survival rate is low. At present, little is known about whether the use of metformin decreases the risk of GC in patients with type 2 diabetes. Therefore, in the present study, a systematic review was performed to analyze the effect of metformin on GC. A literature search was conducted in PubMed, EMBASE, and the Cochrane Library databases for articles published up to June 30th, 2016. The studies that evaluated GC patients treated with metformin and compared them with GC patients treated with other antidiabetic drugs were reviewed. Eligible studies were evaluated using the Newcastle-Ottawa Scale. Adjusted hazard ratio and 95% confidence intervals were determined to evaluate the effect of metformin on GC. From the 422 articles evaluated, 5 studies involving a total of 1,804,479 patients met the inclusion criteria and were qualitatively analyzed. The quality of all selected articles was classified as moderate. These studies reported that the long-term use of metformin was associated with a lower risk of GC compared with the lack of use of metformin or the use of other hypoglycemic drugs. In GC patients with diabetes who were subjected to gastrectomy, the cumulative use of metformin reduced the rates of disease recurrence and of all-cause and cancer-specific mortality. Despite the limited number of studies on this subject, currently available evidence indicates that metformin is associated with a decreased risk of GC and improves survival in patients with type 2 diabetes. However, more well-designed trials are required to elucidate this association.
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Until now, it remains unclear how to best use the histological subtype in clinical practice. This study aimed to compare differences in the efficacy of postoperative chemotherapy among different histological subtypes of colon adenocarcinomas. Using the Surveillance, Epidemiology, and End Results-Medicare database, 51,200 patients with stage II or III primary colon carcinomas who underwent resection for curative intent between 1992 and 2008 were included. The survival benefit was evaluated using a Cox proportional hazards model, interaction analyses, and propensity score-matched techniques. There was no significant difference in survival for low-risk stage II mucinous adenocarcinoma (MA) or nonmucinous adenocarcinoma (NMA) between 5-FU and oxaliplatin-treated groups (P = 0.387 for MA, P = 0.629 for NMA). Patients with high-risk stage II NMA who received the oxaliplatin chemotherapy regimen had significantly improved cancer-specific survival (CSS) compared with the 5-FU group (P = 0.004), while those with MA saw no improvement (P = 0.690). For stage III tumors, patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS compared with the 5-FU group (P < 0.001), while those with MA saw no improvement (P = 0.300). There were significant interactions between chemotherapy regimen and histological subtype. For patients with resected colon cancer who received 5-FU-based postoperative chemotherapy, oxaliplatin chemotherapy prolongs CSS for stage III and high-risk stage II NMA. Conversely, there was no similar improvement with addition of oxaliplatin for patients with stage III or stage II MA.
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Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Oxaliplatino/uso terapéutico , Adenocarcinoma/patología , Adenocarcinoma Mucinoso/patología , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/patología , Femenino , Humanos , Masculino , Oxaliplatino/farmacología , Estudios RetrospectivosRESUMEN
Growing evidence indicates that inflammation plays an important role in cancer progression and prognosis; however, the prognostic role of platelet to lymphocyte ratio (PLR) in colorectal cancer (CRC) is unknown. A cohort of 1845 CRC patients from the Department of Surgical Oncology at The First Hospital of China Medical University (CMU-SO) was retrospectively analyzed. Harrell's concordance index (c-index) was used to determine the optimal cut-off value of PLR and evaluate its predictive ability. Our results from CMU-SO indicated that the overall survival (OS) rate was significantly lower in the high-PLR group compared with the low-PLR group (P = 0.001). A similar result was observed for the cancer-specific survival (CSS) rate between these two groups (P = 0.001). The multivariate analysis indicated that high PLR was an independent prognostic indicator of poor OS (hazard ratio [HR] = 1.356, 95% confidence interval [CI] = 1.117-1.647, P = 0.002) and CSS (HR = 1.364, 95% CI = 1.111-1.675, P = 0.003). In addition, the c-indexes of TNM staging combined with PLR were greater than those of TNM staging alone (OS: 0.768 vs. 0.732; CSS: 0.785 vs. 0.746). In conclusion, elevated PLR is a negative prognostic indicator of CRC and may serve as an additional index of the current TNM staging system for predicting CRC.
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BACKGROUND: Growing evidence has indicated that some inflammatory markers, including lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), can be used as indicators in the prognosis of colorectal cancer (CRC). However, there is controversy concerning what is the best predictor of prognosis in CRC. METHODS: A cohort of 1744 CRC patients in our institution was analyzed retrospectively. Harrell's concordance index (c-index) and Bayesian information criterion (BIC) were used to determine the optimal cut-off values of inflammatory markers and compare their predictive capacity. The association of inflammatory markers with overall survival (OS) and cancer-specific survival (CSS) was analyzed using Kaplan-Meier methods with log-rank test, followed by multivariate Cox proportional hazards model. RESULTS: The multivariate analysis indicated that among these inflammatory markers, NLR (< 2.0 vs. ≥ 2.0) was the only independent prognostic factor for poor OS [hazard ratio (HR) = 0.758, 95% confidence intervals (CI) = 0.598-0.960, P = 0.021)] and CSS (HR = 0.738, 95% CI = 0.573-0.950, P = 0.018). Among these inflammatory markers, the c-index and BIC value for NLR were maximum and minimum for OS, respectively. In addition, the c-index was higher and the BIC value was smaller in TNM staging combined with NLR compared with the values obtained in TNM staging alone. CONCLUSION: NLR is a superior indicator of prognosis compared with LMR, PLR, and PNI in CRC patients, and NLR may serve as an additional indicator based on the current tumor staging system.