5 research outputs found
BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells
Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments
Synthesis and Evaluation of the Cytotoxicities of Tetraindoles: Observation that the 5-Hydroxy Tetraindole (SK228) Induces G<sub>2</sub> Arrest and Apoptosis in Human Breast Cancer Cells
Current chemical and biological interest in indole-3-carbinol
(I3C) and its metabolites has resulted in the discovery of new biologically
active indoles. As part of a program aimed at the development of indole
analogues, tetraindoles <b>1</b>โ<b>15</b> were
prepared and their antiproliferative effects on human breast cancer
cells were evaluated. The results show that the 5-hydroxy-tetraindole <b>8</b> (SK228) has optimum antiproliferative activity against breast
adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity
involves G<sub>2</sub>-phase arrest of the cell cycle with a distinctive
increase in the expression of cyclin B1 and phospho-cdc2. Further
observations suggest that 5-hydroxy-tetraindole <b>8</b> induces
apoptosis through externalization of membrane phosphatidylserine,
DNA fragmentation, and activation of caspase-3. Given the fact that
I3C and its metabolites have been shown to improve therapeutic efficacy
and to have a broad range of antitumor activities in human cancer
cells, the current findings have important pharmacological relevance
as they open a promising route to the development of a potential chemotherapeutic
application of tetraindoles as agents for the treatment of breast
cancer
Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus
The tiger genome and comparative analysis with lion and snow leopard genomes
Tigers and their close relatives (Panthera) are some of the world's most endangered species. Here we report the de novo assembly of an Amur tiger whole-genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats' hypercarnivorous diet and muscle strength. We report a snow leopard-specific genetic determinant in EGLN1 (Met39>Lys39), which is likely to be associated with adaptation to high altitude. We also detect a TYR260G>A mutation likely responsible for the white lion coat colour. Tiger and cat genomes show similar repeat composition and an appreciably conserved synteny. Genomic data from the five big cats provide an invaluable resource for resolving easily identifiable phenotypes evident in very close, but distinct, species.close141