Intravesical instillation of c-MYC inhibitor KSI-3716 suppresses orthotopic bladder tumor growth.

PURPOSE: c-MYC is a promising target for cancer therapy but its use is restricted by unwanted, devastating side effects. We explored whether intravesical instillation of the c-MYC inhibitor KSI-3716 could suppress tumor growth in murine orthotopic bladder xenografts. MATERIALS AND METHODS: The small molecule KSI-3716, which blocks c-MYC/MAX binding to target gene promoters, was used as an intravesical chemotherapy agent. KSI-3716 action was assessed by electrophoretic mobility shift assay, chromatin immunoprecipitation, transcription reporter assay and quantitative reverse transcriptase-polymerase chain reaction. Inhibition of cell proliferation and its mechanism was monitored by cell cytotoxicity assay, EdU incorporation assay and flow cytometry. The in vivo efficacy of KSI-3716 was examined by noninvasive luminescence imaging and histological analysis after intravesical instillation of KSI-3716 in murine orthotopic bladder xenografts. RESULTS: KSI-3716 blocked c-MYC/MAX from forming a complex with target gene promoters. c-MYC mediated transcriptional activity was inhibited by KSI-3716 at concentrations as low as 1 µM. The expression of c-MYC target genes, such as cyclin D2, CDK4 and hTERT, was markedly decreased. KSI-3716 exerted cytotoxic effects on bladder cancer cells by inducing cell cycle arrest and apoptosis. Intravesical instillation of KSI-3716 at a dose of 5 mg/kg significantly suppressed tumor growth with minimal systemic toxicity. CONCLUSIONS: The c-MYC inhibitor KSI-3716 could be developed as an effective intravesical chemotherapy agent for bladder cancer.

The condensin component NCAPG2 regulates microtubule-kinetochore attachment through recruitment of Polo-like kinase 1 to kinetochores.

The early event of microtubule-kinetochore attachment is a critical stage for precise chromosome segregation. Here we report that NCAPG2, which is a component of the condensin II complex, mediates chromosome segregation through microtubule-kinetochore attachment by recruiting PLK1 to prometaphase kinetochores. NCAPG2 colocalizes with PLK1 at prometaphase kinetochores and directly interacts with the polo-box domain (PBD) of PLK1 via its highly conserved C-terminal region. In both humans and Caenorhabditis elegans, when NCAPG2 is depleted, the attachment of the spindle to the kinetochore is loosened and misoriented. This is caused by the disruption of PLK1 localization to the kinetochore and by the decreased phosphorylation of its kinetochore substrate, BubR1. In addition, the crystal structure of the PBD of PLK1, in complex with the C-terminal region of NCAPG2, (1007)VLS-pT-L(1011), exhibits structural conservation of PBD-phosphopeptides, suggesting that the regulation of NCAPG2 function is phosphorylation-dependent. These findings suggest that NCAPG2 plays an important role in regulating proper chromosome segregation through a functional interaction with PLK1 during mitosis.

Sixteenth century Gymnophalloides seoi infection on the coast of the Korean Peninsula.

Gymnophalloides seoi is a trematode species discovered as recently as 1993. Interestingly, ancient G. seoi eggs were identified in our earlier study on a 17th Century female mummy unearthed in a Korean county (HD-1) where G. seoi infection, according to a nationwide survey of 2001, was considered not to have been endemic. Although we suspected that the geographical distribution of G. seoi might have contracted over the past several hundred years from wider coastal areas on the Korean peninsula to the much more restricted region delineated by the survey, there has been only the single, above-noted report of an ancient G. seoi infection in a currently non-endemic area. As such, more evidence is needed before our contraction theory of G. seoi infection prevalence can be confirmed as fact. Our current report in this regard will perhaps help to end the controversy. In a newly discovered 17th Century male mummy found in another Korean county considered non-endemic by the 2001 survey, we identified a large number of ancient G. seoi eggs. We believe that this additional evidence for a wider distribution of G. seoi infection prior to the 20th Century is invaluable support for our earlier hypothesis.