Investigation of Anti-Tumor Effects of an MLK1 Inhibitor in Prostate and Pancreatic Cancers.
Ontology highlight
ABSTRACT:
SUBMITTER: Fan YC
PROVIDER: S-EPMC8389662 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.
| S-EPMC7961597 | biostudies-literature
Project description:Imprime PGG (Imprime) is in late-stage clinical development as a combinatorial agent with several therapeutic modalities. Here we present pre-clinical mechanistic data supportive of Imprime, a soluble yeast β-1,3/1,6-glucan pathogen-associated molecular pattern able to prime innate immune cells in a Dectin-1dependent manner. In tumor-free mice, Imprime evoked broad innate immune responses (type I interferon signature, mobilization of myeloid cells, dendritic cell and monocyte/macrophage expression of co-stimulatory ligands like CD86, and activation of natural killer cells). Imprime-mediated activation of myeloid cells also resulted in functional priming of antigen-specific CD8 T cell response. In tumor-bearing mice, Imprime monotherapy further resulted in activation of systemic and tumor infiltrating macrophages and enhanced cytotoxic CD8 T cell trafficking. Imprime enhanced the anti-tumor activity of several combinatorial agents in mouse cancer models; anti-tyrosinase-related protein 1 antibody in B16F10 melanoma experimental lung metastasis model, anti-vascular endothelial growth factor receptor 2 antibody in H1299 and H441 lung cancer, and anti-programmed cell death protein 1 antibody in MC38 colon cancer models. Mechanistically, combining Imprime with these combinatorial therapeutic agents elicited enhanced innate immune activation, supporting immunological synergy. Finally, Imprime treatment induced similar in vitro phenotypic and functional activation of human innate immune cells. Collectively, these data demonstrate Imprime's potential to orchestrate a broad, yet coordinated, anti-cancer immune response and complement existing cancer immunotherapies.
| S-EPMC9178990 | biostudies-literature
Project description:Pancreatic cancers are currently the fourth leading cause of cancer-related death and new therapies are desperately needed. The most common pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). This report describes the development of therapies, which effectively deplete PDAC cells of their required polyamine growth factors. Of all human tissues, the pancreas has the highest level of the native polyamine spermidine. To sustain their high growth rates, PDACs have altered polyamine metabolism, which is reflected in their high intracellular polyamine levels and their upregulated import of exogenous polyamines. To understand how these cancers respond to interventions that target their specific polyamine pools, L3.6pl human pancreatic cancer cells were challenged with specific inhibitors of polyamine biosynthesis. We found that pancreatic cell lines have excess polyamine pools, which they rebalance to address deficiencies induced by inhibitors of specific steps in polyamine biosynthesis (e.g., ornithine decarboxylase (ODC), spermidine synthase (SRM), and spermine synthase (SMS)). We also discovered that combination therapies targeting ODC, SMS, and polyamine import were the most effective in reducing intracellular polyamine pools and reducing PDAC cell growth. A combination therapy containing difluoromethylornithine (DFMO, an ODC inhibitor) and a polyamine transport inhibitor (PTI) were shown to significantly deplete intracellular polyamine pools. The additional presence of an SMS inhibitor as low as 100 nM was sufficient to further potentiate the DFMO + PTI treatment.
| S-EPMC5753661 | biostudies-literature
Project description:Prostate cancer is the second most prevalent malignancy worldwide. In the early stages, the development of prostate cancer is dependent on androgens. Over time with androgen deprivation therapy, 20% of prostate cancers progress to a castration-resistant form. Novel treatments for prostate cancers are still urgently needed. Erianin is a plant-derived bibenzyl compound. We report herein that erianin exhibits anti-tumor effects in androgen-sensitive and castration-resistant prostate cancer cells through different mechanisms. Erianin induces endoplasmic reticulum stress-associated apoptosis in androgen-sensitive prostate cancer cells. It also triggers pro-survival autophagic responses, as inhibition of autophagy predisposes to apoptosis. In contrast, erianin fails to induce apoptosis in castration-resistant prostate cancer cells. Instead, it results in cell cycle arrest at the M phase. Mechanistically, C16 ceramide dictates differential responses of androgen-sensitive and castration-resistant prostate cancer cells to erianin. Erianin elevates C16 ceramide level in androgen-sensitive but not castration-resistant prostate cancer cells. Overexpression of ceramide synthase 5 that specifically produces C16 ceramide enables erianin to induce apoptosis in castration-resistant prostate cancer cells. Our study provides both experimental evidence and mechanistic data showing that erianin is a potential treatment option for prostate cancers.
| S-EPMC8484793 | biostudies-literature
Project description:Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4(+) T cells and CD4(+) forkhead box P3 (FoxP3)(+) regulatory T cells (Treg) but reduced numbers of CD8(+) T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8(+) T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
| S-EPMC3787053 | biostudies-literature
Project description:Either metformin or liraglutide has been reported to have anti-tumor effects on pancreatic cancer cells. However, it is not clear whether their combined treatment has additive or synergistic anti-tumor effects on pancreatic cancer cells. In this study, the human pancreatic cancer cell line MiaPaca-2 was incubated with liraglutide and/or metformin. The cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound-healing and transwell migration assays were used to detect cell viability, clonogenic survival, cell cycle and cell migration, respectively. RT-PCR and western blot analyses were used to determine the mRNA and protein levels of related molecules. Results showed that combination treatment with liraglutide (100 nmol/L) and metformin (0.75 mmol/L) significantly decreased cell viability and colony formation, caused cell cycle arrest, upregulated the level of pro-apoptotic proteins Bax and cleaved caspase-3, and inhibited cell migration in the cells, although their single treatment did not exhibit such effects. Combination index value for cell viability indicated a synergistic interaction of liraglutide and metformin. Moreover, the combined treatment with liraglutide and metformin could activate the phosphorylation of AMP-activated protein kinase (AMPK) more potently than their single treatment in the cells. These results suggest that liraglutide in combination with metformin has a synergistic anti-tumor effect on the pancreatic cancer cells, which may be at least partly due to activation of AMPK signaling. Our study provides new insights into the treatment of patients with type 2 diabetes and pancreatic cancer.
| S-EPMC5999272 | biostudies-literature
Project description:Cancer drug researchers have been seeking microtubule-inhibiting agents (MIAs) with higher bioactivity and lower toxicity than currently marketed drugs. WX-132-18B, a novel structural compound synthesized at our institute, specifically bound to the colchicine-binding site on tubulin rather than the vinblastine site, and concentration-dependently reduced microtubule content via depolymerization. It exhibited the same cellular phenotypic profiles as the classic MIAs (colchicine, vincristine, and taxol), including inducing cell cycle arrest at the G2/M phase, triggering tumor cell apoptosis, promoting nuclear membrane permeability, reducing mitochondrial membrane potential, and disrupting the redox system balance. Importantly, WX-132-18B displayed more potent in vitro bioactivity (IC50 0.45-0.99 nM) than did the classic MIAs; it inhibited the proliferation of human umbilical vein endothelial cells and seven types of human tumor cells, especially the taxol-resistant breast cancer cells MX-1/T. WX-132-18B also dose-dependently inhibited mice sarcoma, human lung, and gastric cancer xenograft tumors and the formation of tumor blood vessels in mice. In conclusion, WX-132-18B is a novel microtubule-depolymerizing agent that selectively acts on the colchicine-binding site of tubulin and exerts potent in vitro and in vivo anti-tumor effects. These characteristics, along with its anti-angiogenesis and anti-drug resistance properties, make WX-132-18B a promising anti-tumor drug candidate.
| S-EPMC5641089 | biostudies-other
Project description:Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that regulates a plethora of downstream signaling pathways essential for cell migration, proliferation and death, processes that are exploited by cancer cells during malignant progression. These well-established tumorigenic activities, together with its high expression and activity in different cancer types, highlight FAK as an attractive target for cancer therapy. We have assessed and characterized the therapeutic potential and the biological effects of BI 853520, a novel small chemical inhibitor of FAK, in several preclinical mouse models of breast cancer. Treatment with BI 853520 elicits a significant reduction in primary tumor growth caused by an anti-proliferative activity by BI 853520. In contrast, BI 853520 exerts effects with varying degrees of robustness on the different stages of the metastatic cascade. Together, the data demonstrate that the repression of FAK activity by the specific FAK inhibitor BI 853520 offers a promising anti-proliferative approach for cancer therapy.
| S-EPMC6148276 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-02-07 | GSE255309 | GEO
Project description:Intake of probiotics or fermented food produced by some probiotic bacteria is believed to exert anti-tumor functions in various cancers, including pancreatic cancer, because several studies have demonstrated the anti-tumor effects of probiotic bacteria in vitro and in vivo in animal carcinogenesis models. However, the mechanisms underlying the anticancer effects of probiotics on pancreatic cancer have not been clarified. In this study, we assessed the anti-tumor effects of probiotic bacteria against pancreatic cancer cells. Among the known probiotic bacteria, Aspergillus oryzae exhibited a strong pancreatic tumor suppression effect. The culture supernatant of A. oryzae was separated by HPLC. Heptelidic acid was identified as an anti-tumor molecule derived from A. oryzae by LC-MS and NMR analysis. The anti-tumor effect of heptelidic acid was exhibited in vitro and in vivo in a xenograft model of pancreatic cancer cells. The anti-tumor effect of heptelidic acid was exerted by the p38 MAPK signaling pathway. Heptelidic acid traverses the intestinal mucosa and exerts anti-tumor effects on pancreatic cancer cells. This is a novel anti-tumor mechanism induced by beneficial bacteria against pancreatic cancer in which bacterial molecules pass through the intestinal tract, reach the extra-intestinal organs, and then induce apoptosis via an inducible signaling pathway.
| S-EPMC8154913 | biostudies-literature