Isobolographic Analysis Demonstrates the Additive and Synergistic Effects of Gemcitabine Combined with Fucoidan in Uterine Sarcomas and Carcinosarcoma Cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Bobinski M
PROVIDER: S-EPMC7017062 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
Publications
Isobolographic Analysis Demonstrates the Additive and Synergistic Effects of Gemcitabine Combined with Fucoidan in Uterine Sarcomas and Carcinosarcoma Cells.
Bobiński Marcin M Okła Karolina K Łuszczki Jarogniew J Bednarek Wiesława W Wawruszak Anna A Moreno-Bueno Gema G Dmoszyńska-Graniczka Magdalena M Tarkowski Rafał R Kotarski Jan J
Cancers 20191231 1
<b>Keywords: </b>. ...[more]
Similar Datasets
Project description:The aim of the study was to assess the activity of fucoidan on the uterine sarcomas (MES-SA and ESS-1) and carcinosarcoma cell lines (SK-UT-1 and SK-UT-1B) and its toxicity on the human skin fibroblasts (HSF). Two uterine sarcomas and two carcinosarcoma cell lines were examined, as a control HSF were used. Cell viability was assessed with MTT test, apoptosis with caspase-3 activity and cell cycle by assessment of DNA synthesis. Fucoidan significantly decreases cell viability in SK-UT-1, SK-UT-1B, and ESS-1 cell lines, such effect was not observed in MES-SA. Fucoidan was not substantially affecting proliferation among normal cells. The tested agent induced apoptosis in all cell cultures used in the experiment. Fucoidan affects cell cycle of all tested cell lines except MES-SA by increasing percentage of cells in G0/sub-G1/G1 phase. Fucoidan do not only affect proliferation but induces apoptosis in selected uterine sarcoma and carcinosarcoma cell lines, so it has potential to be used as cytotoxic agent. Fucoidan seems to be promising anti-cancer agent for endometrial stromal sarcoma and carcinosarcoma.
| S-EPMC6420609 | biostudies-literature
Project description:Uterine carcinosarcoma (UCS) is a rare but aggressive endometrial cancer. Survival outcomes for women diagnosed with UCS remain poor with lower survival than those of endometrioid or high-grade serous uterine cancers. The histopathological hallmark of carcinosarcoma is the presence of both sarcomatous and carcinomatous elements. The survival rates for UCS have not improved for over 40 years; therefore, there is a profound need to identify new treatments. To investigate novel chemotherapy treatment combinations for UCS, we generated a UCS patient-derived organoid (PDO) cell line from a patient that received neoadjuvant treatment with paclitaxel and carboplatin. The PDO cell line (UCS1) was grown in three-dimensional domes. The PDO domes were treated with six individual chemotherapies or nine combinations of those six drugs. Cell death in response to chemotherapy was assessed. We found that the six monotherapies had minimal effectiveness at inducing cell death after 48 h of treatment. The combination of paclitaxel and carboplatin (which is the standard-of-care chemotherapy treatment for UCS) led to a small increase in apoptosis compared with the monotherapies. Importantly, when either carboplatin or paclitaxel was combined with gemcitabine, there was an appreciable increase in cell death. In conclusion, for the UCS1 patient-derived tumor cells, gemcitabine combinations were more effective than carboplatin/paclitaxel. Our data support the use of PDOs to predict responses to second-line chemotherapy.
| S-EPMC10966467 | biostudies-literature
Project description:PurposeIron metabolism and ferroptosis play crucial roles in the pathogenesis of cancer. In this study, we aim to study the role of ferroptosis-related genes (FRGs) in uterine carcinosarcoma (UCS) and identify potential target for UCS.MethodsPrognostic differentially expressed FRGs were identified of in the TCGA cohort. Integrated analysis, cox regression, and the least absolute shrinkage and selection operator (LASSO) methods of FRGs were performed to construct a multigene signature prognostic model. Moreover, a dataset from Gene Expression Omnibus (GEO) served as an external validation. HSF1 was knockdown in MES-SA and FU-MMT-1 cells, and cell viability, lipid ROS, and intracellular iron level were detected when combined with doxorubicin or gemcitabine.ResultFive FRGs were selected to construct a prognostic model of UCS. The group with high-risk signature score exhibited obviously lower overall survival (OS) than the group with low risk signature score in both TCGA and validated GEO cohorts. Multivariate Cox regression analysis further indicated that the risk score was an independent factor for the prognosis of UCS patients. The high-risk group of UCS has a higher sensitivity in the treatment of doxorubicin and gemcitabine. Knocking down of HSF1 in MES-SA and FU-MMT-1 cells was more sensitive to doxorubicin and gemcitabine via increasing ferroptosis.ConclusionsThe five FRGs risk signature prognostic model having a superior and drug sensitivity predictive performance for OS in UCS, and HSF1 is a potential marker sensitive to doxorubicin and gemcitabine in UCS patients.
| S-EPMC8769820 | biostudies-literature
Project description:We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.
| S-EPMC5599133 | biostudies-literature
Project description:Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGF?) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGF? at 19q13.1 prompted us to investigate the role of TGF? signaling in UCS.Here we demonstrated the components of TGF? pathway are expressed and functional in UCS. TGF?-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGF? receptor I (TGF?R-I) or TGF? receptor I/II (TGF?R-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGF?-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGF?-I. Inhibition of NFAT-1 or TGF?R-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGF? the TGF?R-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGF?R-I could be efficacious in treatment of UCS.
| S-EPMC4546494 | biostudies-literature
Project description:Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-? (TGF?) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-? receptor-I (TGF?R1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-?1 (TGF?1) reduces cellular viability, invasion, clonal growth and differentiation. Interestingly, GLT sensitizes UCS cells to chemotherapy both in vitro and in in vivo preclinical tumor model. Hence, targeting TGF? signaling, in combination with standard chemotherapy, may be exploited as an important strategy to manage the clinically challenging UCS.
| S-EPMC7590842 | biostudies-literature
Project description:Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) are two rare histologic variants of uterine carcinoma, with distinct molecular profiles and aggressive metastatic potential. As the effectivity of traditional platinum-based chemotherapy for USC and UCS is low, and there are high rates of resistance and recurrence, the development of novel targeted therapeutics is needed. Human epidermal growth factor receptor 2 (HER2) has proven to be an oncogene of increasing interest in these cancers, as HER2 protein overexpression and/or c-ERBB2 gene amplification ranges from ~30 to 35% in USC, and between ~15 and 20% in UCS. This review summarizes the existing clinical and preclinical evidence, as well as ongoing clinical trials of HER2-targeting therapeutics, and identifies potential areas of further development and inquiry.
| S-EPMC10452357 | biostudies-literature
Project description:Uterine carcinosarcomas are rare and extremely aggressive undifferentiated carcinomas which include both carcinomatous and sarcomatous elements. A 52-year-old female presented with heavy irregular menstrual bleeding for several years and new right elbow pain and swelling. Ultrasound and computed tomography showed a large uterine mass with regional and distant metastatic lymphadenopathy and suspicious findings of osseous metastasis to the right elbow. A biopsy confirmed uterine carcinosarcoma, and the patient underwent chemotherapy and then surgical resection of the uterine mass with palliative radiotherapy of the right elbow. The postoperative imaging showed new metastasis, and the patient was scheduled to start on immunotherapy. Considering the highly invasive nature of uterine carcinosarcomas, timely detection of this cancer using characteristic imaging and pathology findings is of extreme importance to improve the patient's survival.
| S-EPMC7455848 | biostudies-literature
Project description:Uterine carcinosarcoma (UCS) is a rare but lethal neoplasm with high metastasis and recurrence rate, and to date, no molecular classification of UCS has been defined to achieve targeted therapies. In this study, we identified two distinct molecular subtypes of UCS with distinct gene expression patterns and clinicopathologic characteristics. Subtype I UCS recapitulates low-grade UCS, in contrast subtype II UCS represents high-grade UCS with higher tumor invasion rate and tumor weight. Interestingly, subtype I UCS is characterized by cell adhesion and apoptosis pathways, whereas genes over-expressed in subtype II UCS are more involved in myogenesis/muscle development. We also proposed certain potential subtype specific therapeutic targets, such as SYK (spleen tyrosine kinase) for subtype I and cell-cycle proteins for subtype II. Our findings provide a better recognition of UCS molecular subtypes and subtype specific oncogenesis mechanisms, and can help develop more specific targeted treatment options for these tumors.
| S-EPMC5362530 | biostudies-literature
Project description:AimsTo characterise the genetic alterations in adult primary uterine rhabdomyosarcomas (uRMSs) and to investigate whether these tumours are genetically distinct from uterine carcinosarcomas (UCSs).Methods and resultsThree tumours originally diagnosed as primary adult pleomorphic uRMS were subjected to massively parallel sequencing targeting 468 cancer-related genes and RNA-sequencing. Mutational profiles were compared with those of UCSs (n = 57) obtained from The Cancer Genome Atlas. Sequencing data analyses were performed using validated bioinformatic approaches. Pathogenic TP53 mutations and high levels of genomic instability were detected in the three cases. uRMS1 harboured a likely pathogenic YTHDF2-FOXR1 fusion. uRMS2 harboured a PPP2R1A hotspot mutation and amplification of multiple genes, including WHSC1L1, FGFR1, MDM2, and CCNE1, whereas uRMS3 harboured an FBXW7 hotspot mutation and an ANKRD11 homozygous deletion. Hierarchical clustering of somatic mutations and copy number alterations revealed that these tumours initially diagnosed as pleomorphic uRMSs and UCSs were similar. Subsequent comprehensive pathological re-review of the three uRMSs revealed previously unidentified minute pan-cytokeratin-positive atypical glands in one case (uRMS3), favouring its reclassification as UCS with extensive rhabdomyosarcomatous overgrowth.ConclusionsAdult pleomorphic uRMSs harbour TP53 mutations and high levels of copy number alterations. Our findings underscore the challenge in discriminating between uRMS and UCS with rhabdomyosarcomatous differentiation.
| S-EPMC8286280 | biostudies-literature