ABSTRACT
The ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene is associated with Alzheimer's disease (AD) risk in populations of African, Asian, and European ancestry1-5. Numerous ABCA7 mutations contributing to risk have been identified, including a 44 base pair deletion (rs142076058) specific to individuals of African ancestry and predicted to cause a frameshift mutation (p.Arg578Alafs) (Cukier et al., 2016). The UMi043-A human induced pluripotent stem cell line was derived from an African American individual with AD who is heterozygous for this deletion and is a resource to further investigate ABCA7 and how this African-specific deletion may influence disease pathology.
Subject(s)
Alzheimer Disease , Cell Line , Induced Pluripotent Stem Cells , Humans , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , ATP-Binding Cassette Transporters/genetics , Black or African American/genetics , Induced Pluripotent Stem Cells/cytology , MutationABSTRACT
High rates of recurrence and treatment resistance in the most common malignant adult brain cancer, glioblastoma (GBM), suggest that monotherapies are not sufficiently effective. Combination therapies are increasingly pursued, but the possibility of adverse drug-drug interactions may preclude clinical implementation. Developing single molecules with multiple targets is a feasible alternative strategy to identify effective and tolerable pharmacotherapies for GBM. Here, we report the development of a novel, first-in-class, dual aurora and lim kinase inhibitor termed F114. Aurora kinases and lim kinases are involved in neoplastic cell division and cell motility, respectively. Due to the importance of these cellular functions, inhibitors of aurora kinases and lim kinases are being pursued separately as anti-cancer therapies. Using in vitro and ex vivo models of GBM, we found that F114 inhibits GBM proliferation and invasion. These results establish F114 as a promising new scaffold for dual aurora/lim kinase inhibitors that may be used in future drug development efforts for GBM, and potentially other cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Lim Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aurora Kinase A/metabolism , Aurora Kinase B/metabolism , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Lim Kinases/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The UMi028-A-2 human induced pluripotent stem cell line carries a homozygous mutation (rs377155188, C>G, p.S1038C) in the tetratricopeptide repeat domain 3 (TTC3) gene that was introduced via CRISPR/Cas9 genome editing. The line was originally derived from a neurologically normal male and has been thoroughly characterized following editing. The p.S1038C variant has been shown to potentially contribute to the risk of late onset Alzheimer's disease and is a resource to further investigate the consequences of TTC3 and this alteration in disease pathology.
Subject(s)
Alzheimer Disease , Induced Pluripotent Stem Cells , Alzheimer Disease/genetics , CRISPR-Cas Systems/genetics , Cell Line , Gene Editing , Humans , Male , Ubiquitin-Protein LigasesABSTRACT
Leishmaniasis is a vector-borne disease caused by infection by parasites from the genus Leishmania. Clinical manifestations can be visceral or cutaneous, the latter mainly being chronic ulcers. This work was aimed at evaluating Calliphoridae Lucilia sericata- and Sarconesiopsis magellanica-derived larval excretions and secretions' (ES) in vitro anti-leishmanial activity against Leishmania panamensis. Different larval-ES concentrations from both blowfly species were tested against either L. panamensis promastigotes or intracellular amastigotes using U937-macrophages as host cells. The Alamar Blue method was used for assessing parasite half maximal inhibitory concentration (IC50) and macrophage cytotoxicity (LC50). The effect of larval-ES on L. panamensis intracellular parasite forms was evaluated by calculating the percentage of infected macrophages, parasite load and toxicity. L. sericata-derived larval-ES L. panamensis macrophage LC50 was 72.57µg/mL (65.35-80.58µg/mL) and promastigote IC50 was 41.44µg/mL (38.57-44.52µg/mL), compared to 34.93µg/mL (31.65-38.55µg/mL) LC50 and 23.42µg/mL (22.48-24.39µg/mL) IC50 for S. magellanica. Microscope evaluation of intracellular parasite forms showed that treatment with 10µg/mL L. sericata ES and 5µg/mL S. magellanica ES led to a decrease in the percentage of infected macrophages and the amount of intracellular amastigotes. This study produced in vitro evidence of the antileishmanial activity of larval ES from both blowfly species on different parasitic stages and showed that the parasite was more susceptible to the ES than it's host cells. The antileishmanial effect on L. panamensis was more evident from S. magellanica ES.
