Histone deacetylase inhibitors (HDACi) are established anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimization program yielded HDACi with nanomolar inhibitory activity against histone deacetylase class I/IIb enzymes.
View Article and Find Full Text PDFCentral nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2-dimensional cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia.
View Article and Find Full Text PDFPilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-based proteomic profiling to molecularly characterize PA tissue samples from 62 patients.
View Article and Find Full Text PDFBackground: New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. To uncover novel potentiators of T cell anti-tumor immunity, we carried out an ex vivo pharmacological screen and identified 5-Nonyloxytryptamine (5-NL), a serotonin agonist, as increasing the ability of T cells to target tumor cells.
Methods: The pharmacological screen utilized lymphocytic choriomeningitis virus (LCMV)-primed splenic T cells and melanoma B16.
Viral-based cancer therapies have tremendous potential, especially in the context of treating poorly infiltrated cold tumors. However, in tumors with intact anti-viral interferon (IFN) pathways, while some oncolytic viruses induce strong innate and adaptive immune responses, they are neutralized before exerting their therapeutic effect. Arenaviruses, particularly the lymphocytic choriomeningitis virus (LCMV) is a noncytopathic virus with preferential cancer tropism and evolutionary mechanisms to escape the immune system for longer and to block early clearance.
View Article and Find Full Text PDFEmerging evidence indicates B-cell activating factor (BAFF, ) to be an important cytokine for antitumor immunity. In this study, we generated a BAFF-overexpressing B16.F10 melanoma cell model and found that BAFF-expressing tumors grow more slowly than control tumors.
View Article and Find Full Text PDFA disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells.
View Article and Find Full Text PDFSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 and is responsible for the ongoing pandemic. Screening of potential antiviral drugs against SARS-CoV-2 depend on in vitro experiments, which are based on the quantification of the virus titer. Here, we used virus-induced cytopathic effects (CPE) in brightfield microscopy of SARS-CoV-2-infected monolayers to quantify the virus titer.
View Article and Find Full Text PDFThe inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies.
View Article and Find Full Text PDFDipyridamole, an antiplatelet drug, has been shown to synergize with statins to induce cancer cell-specific apoptosis. However, given the polypharmacology of dipyridamole, the mechanism by which it potentiates statin-induced apoptosis remains unclear. Here, we applied a pharmacological approach to identify the activity of dipyridamole specific to its synergistic anticancer interaction with statins.
View Article and Find Full Text PDFBackground: New therapies are urgently needed in melanoma particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors.
Methods: Drug screening, IC50 determinations as well as synergy assays were detected by the MTT assay. Apoptosis using Annexin V and 7AAD staining was assessed using flow cytometry.