Impact of the glutathione synthesis pathway on sulfasalazine-treated endometrial cancer.
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ABSTRACT:
SUBMITTER: Sendo K
PROVIDER: S-EPMC8794577 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Stage IIIA endometrial cancer includes patients with serosal or adnexal invasion and patients with positive peritoneal cytology only. In this study, we assessed the impact of peritoneal cytology on endometrial cancer survival. All endometrial cancer patients receiving surgery and radiotherapy at the Geneva University Hospitals between 1980 and 1993 were included. Stage IIIA cancers were categorised into 'cytological' stage IIIA (only positive peritoneal cytology) and 'histological' stage IIIA (serosal or adnexal infiltration). Survival rates were analysed by Kaplan-Meier method and compared using log-rank test. The prognostic importance of peritoneal cytology was analysed by multivariate regression analysis. This study included 170 endometrial cancers (112 stage I, 17 cytological stage IIIA, 18 histological stage IIIA, 9 stage IIIB+). Disease-specific survival of cytological stage IIIA was not different from stage I (94 vs 88% respectively, P=0.5) but better than histological stage IIIA (94 vs 51% respectively, P<0.01). Histological stage IIIA patients were at increased risk to die from cancer compared to stage I patients (HR 2.7, 95% CI 1.0-7.7), while cytological stage IIIA patients were not (HR 0.3, 95% CI 0.3-2.0). Cytological stage IIIA endometrial cancer has similar prognosis as stage l and better prognosis than histological stage IIIA. Additional research, definitively separating stage and cytology is warranted.
| S-EPMC2376850 | biostudies-other
Project description:Recent research has identified an important role for a cystine-glutamate antiporter (system Xc) in the biology of malignant brain tumors. This transporter is effectively inhibited by sulfasalazine, a drug widely used to treat a number of chronic inflammatory conditions such as Crohn's disease. Preclinical data show that sulfasalazine is an effective inhibitor of tumor growth and tumor-associated seizures. These studies suggest that the cystine-glutamate antiporter is a valuable drug target for which tumor-specific drugs can be generated. In the meantime, sulfasalazine may be considered as adjuvant treatment for malignant gliomas.
| S-EPMC3644176 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) results from alterations in intestinal flora and the immune system. Sulfasalazine (SASP) is a sulfa antimicrobial used to treat IBD in clinic for years. However, how SASP affects gut microbes and its potential functions remains unclear. To investigate the relationships of SASP, IBD, and gut microbiome, we used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis in rats, and analyzed the microbiota in the fecal samples, which come from the control group (treated with ethanol + saline), the model group (treated with TNBS-ethanol + saline) and the SASP group (treated with TNBS-ethanol + SASP), with 16S gene sequencing and followed up a subset sample using shotgun sequencing. The study found that SASP treatment could not only restore the TNBS-induced gut dysbiosis, which was proved by the increasing amount of SCFAs-producing bacteria and lactic acid-producing bacteria as well as the decreasing amount of Proteobacteria, but also modulate the dysregulated function of the TNBS-induced colitis to resemble that of the control group, including an increased capacity for basic metabolism (carbohydrate metabolism, citrate cycle) and a decrease in the oxidative stress (riboflavin, sulfur, cysteine) as well as bacterial pathogenesis (cell motility and secretion, bacterial motility proteins, flagellar assembly). Moreover, a higher proportion of Mycoplasma was observed in the SASP group, which may associate with infertility. In all, the study provides insight into specific microbial clades and pathways linked with SASP treatment to elaborate the mechanism for treatment of IBD.
| S-EPMC5594074 | biostudies-literature
Project description:To assess the impact of CD133 expression on the prognosis of endometrioid endometrial carcinoma (EEC). We retrospectively assessed CD133 expression in tissue microarray of 116 surgically treated FIGO I-III EEC. Tumors with ≥10% of CD133-expressing cells were considered CD133-positive (CD133+). On the basis of CD133 expression, clinical and pathological parameters, progression-free survival (PFS) and overall survival (OS) were evaluated. Of the EEC studied 85.2% showed CD133-expressing cells. Only 61% (n = 66) of EEC presented ≥10% of CD133 expressing cells and were considered CD133+. The mean OS for CD133+ tumour patients was 161 months (95% CI, 154-168) as compared with 146 months (95% CI, 123-160) for those with CD133- tumors (p = 0.012). The mean PFS for CD133+ tumour was 159 months (95% CI, 149-168) as compared with 147 months (95% CI, 132-161) in those with a CD133-tumour (p = 0.014). CD133+ tumours were less likely to have vascular invasion (p = 0.010) and more likely to be well differentiated (p = 0.034). C133+ tumours predicted favorable OS and PFS of EEC patients, with a Hazard Ratio 4.731 (95% CI, 1.251-17.89; p = 0.022). CD133+ tumor status correlates with favorable prognosis of EEC. Our findings are in agreement with studies addressing brain and colorectal tumours.
| S-EPMC5550511 | biostudies-other
Project description:Simple Summary This multicenter retrospective study aimed to describe the outcomes of patients with endometrial cancer after central pelvic/vaginal relapse treated with radical radiotherapy (RT). We included 139 patients with a median follow-up time of 6.66 years. Patients were treated with external beam radiotherapy to elective pelvic lymph-node regions and boost to the pelvic tumor. During follow-up, 55 (39.6%) patients developed a second relapse, the majority (75%) with disease sites outside the radiation field. Risk group at primary diagnosis and type of boost administration were independent predictors of progression-free and overall survival. Five-year overall survival for the whole cohort was 68% (95% CI: 59–75%). The majority of isolated pelvic recurrences in RT-naive women with EC can be successfully salvaged by RT but survival in high-risk patients remains suboptimal. Individualizing of adjuvant treatment in first line and better treatment alternatives at relapse are important to ultimately improve survival. Abstract (1) Background: This study evaluated the clinical outcome after salvage radiotherapy for first pelvic relapse after endometrial cancer (EC). (2) Methods: This multicenter retrospective study included EC patients with first central pelvic relapse without lymph node involvement treated with curative intent. Progression-free (PFS) and overall survival (OS) were calculated with the Kaplan–Meier method and possible predictive factors for risk of relapse and mortality were identified using the Cox model. (3) Results: We included 139 patients with median EQD2 (Equivalent Dose in 2 Gy fractions) to the clinical target volume of 70.0 Gy. During follow up of median 6.66 years, 39.6% patients developed a second relapse. Risk group classification at primary diagnosis based on histology, grading and FIGO stage and how the pelvic tumor boost was administered were independently associated with PFS and OS. Five-year OS was 68% (95% CI (59–75)) for the whole cohort. Five-year OS was 88% (95% CI (75–94)), 72% (95% CI (55–84)) and 38% (95% CI (15–60)) for the stage I low-, intermediate- and high-risk group, respectively. (4) Conclusions: The majority of central pelvic recurrences in RT-naive EC women can be successfully salvaged with radiotherapy. However, survival in patients with high-risk disease remains poor and warrants a more individualized approach to optimize outcome.
| S-EPMC8002978 | biostudies-literature
Project description:Metabolic enzyme-genes (MEs) play critical roles in various types of cancers. However, MEs have not been systematically and thoroughly studied in pancreatic cancer (PC). Global analysis of MEs in PC will help us to understand PC progressing and provide new insights into PC therapy. In this study, we systematically analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) (n = 180 + 4) and GSE15471 (n = 36 + 36) and discovered that metabolic pathways are disordered in PC. Co-expression network modules of MEs were constructed using weighted gene co-expression network analysis (WGCNA), which identified two key modules. Both modules revealed that the glutathione signaling pathway is disordered in PC and correlated with PC stages. Notably, glutathione peroxidase 2 (GPX2), an important gene involved in glutathione signaling pathway, is a hub gene of the key modules. Analysis of immune microenvironment components reveals that PC stage is associated with M2 macrophages, the marker gene of which is significantly correlated with GPX2. The results indicated that GPX2 is associated with PC progression, providing new insights for future targeted therapy.
| S-EPMC9204196 | biostudies-literature
Project description:To examine the potential correlation between chemotherapy and the risk of individual of second primary endometrial cancer (SEC) in patients with rectal cancer (RC) and assess survival outcomes. The study employed the Surveillance, Epidemiology, and End Results database (SEER) as the primary data source, it encompasses a substantial cohort of patients diagnosed with RC between 1975 and 2018. This study involved a total of 30,847 individuals diagnosed with RC, of whom 168 individuals (5.45‰) experienced SEC. Among them, 107 patients (3.47‰) received chemotherapy treatment, while 61 patients (1.98‰) did not receive chemotherapy. The analysis of the overall occurrence of SEC revealed a significant association between SEC and chemotherapy treatment. Univariate and multivariate analyses confirmed a significant association between chemotherapy treatment and an increased risk of developing SEC in RC patients. Upon implementation of a dynamic analysis on the variables of relative risk and standardized incidence ratios, the results revealed that the likelihood of SEC escalated in tandem with advancing age. The examination of patients who developed SEC after receiving and not receiving chemotherapy revealed no substantial disparities in the 10-year overall survival (OS) and (cancer-specific survival) CSS rates. The results were the same after propensity score matching. Nevertheless, a notable discrepancy emerged when comparing the OS and CSS rates at 10 years between patients afflicted with SEC subsequent to chemotherapy and those afflicted with primary endometrial cancer, and the result was the same situation in the no-chemotherapy group. The use of chemotherapy in RC patients has been associated with an increased probability of developing specific SEC. Therefore, it is imperative to prioritize efforts aimed at reducing chemotherapy-related SEC occurrences and improving the prognosis of affected individuals.
| S-EPMC11319440 | biostudies-literature
Project description:PURPOSE:Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110? signaling for survival. EXPERIMENTAL DESIGN:Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110?, and p110? isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. RESULTS:EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110? inhibitors GSK2636771 and AZD6482, and only in combination with the p110? selective inhibitor A66 was a decrease in cell viability observed. CONCLUSIONS:Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110? alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required.
| S-EPMC3700760 | biostudies-literature
Project description:Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls.Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.
| S-EPMC3677562 | biostudies-literature
Project description:BackgroundAlthough the guidelines recommend gynecological assessment and close monitoring for symptoms of endometrial cancer in postmenopausal breast cancer survivors taking tamoxifen (TAM), the risk of endometrial cancer in young breast cancer survivors has not yet been fully assessed. This study aimed to investigate the risk of developing endometrial cancer and the frequencies of gynecological examinations in young breast cancer survivors taking TAM in South Korea.MethodsA nationwide retrospective cohort study was conducted using the Health Insurance Review and Assessment Service claims data. Kaplan-Meier analyses and log-rank tests were used to assess the probability of endometrial cancer, benign endometrial conditions, and the probability of invasive endometrial procedure. To analyze the risk of endometrial cancer and benign endometrial conditions, we used a multivariable Cox proportional hazards regression model.ResultsBetween 2010 and 2015, 60,545 newly diagnosed female breast cancer survivors were included. The total person-years were 256,099 and 140 (0.23%) patients developed endometrial cancer during the study period. In breast cancer survivors aged ≥60 years [hazard ratio (HR), 5.037; 95% confidence interval (CI), 2.185-11.613], 50-59 years (HR, 4.343; 95% CI, 2.122-8.891), and 40-49 years (HR, 2.121; 95% CI, 1.068-4.213), TAM was associated with an increased risk of endometrial cancer. In subjects aged below 40 years, TAM did not significantly increase the risk of endometrial cancer. However, among the TAM subgroups, breast cancer survivors aged below 40 years [1.61 per 1,000 person-years (PY); HR, 12.460; 95% CI, 2.698-57.522] and aged 40-49 years (2.22 per 1,000 PY; HR, 9.667; 95% CI, 4.966-18.819) with TAM-related endometrial diseases showed significantly increased risks of endometrial cancer. Among the TAM subgroup with benign endometrial conditions, the ratios of the frequency of invasive diagnostic procedures to the incidence of endometrial cancer were higher in subjects under 40 than subjects aged 60 or more.ConclusionYoung breast cancer survivors with TAM-related benign endometrial diseases are at a higher risk of developing endometrial cancer. Gynecological surveillance should be tailored to the risk of endometrial cancer in young breast cancer survivors to improve the early detection of endometrial cancer and avoid unnecessary invasive procedures.
| S-EPMC8209428 | biostudies-literature