xk-469 has been researched along with Colonic-Neoplasms* in 2 studies
2 other study(ies) available for xk-469 and Colonic-Neoplasms
| Article | Year |
|---|---|
Mitotic arrest induced by XK469, a novel antitumor agent, is correlated with the inhibition of cyclin B1 ubiquitination.
XK469 (NSC 697887) is a novel antitumor agent with broad activity against a variety of tumors. Previous studies suggest that XK469 is a topoisomerase II beta poison with functional activity similar to that of 4'-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA). The goal of our study was to investigate its mechanism of action further using a human HCT-116 (H116) colon tumor cell model. Concentration-survival curves with continuous exposure indicated that XK469 had low cytotoxic activity against H116 cells. Cell cycle analysis revealed that XK469 is a phase-specific cell cycle blocker that is associated with increased levels of cyclin B1, cyclin A and p53 but not CDK1 (cdc2) or cyclin E. In contrast, treatment of H116 cells with m-AMSA caused a total degradation of both cyclin A and B1 but enhanced expression of cyclin E and p53. Accumulation of cyclin B1 in XK469-treated cells was correlated with the inhibition of cyclin B1 ubiquitination, a metabolic process mandatory for proteasome-mediated protein turnover. However, no inhibition of cyclin B1 ubiquitination was detected in cells treated with m-AMSA or colchicine, a known mitotic inhibitor. Furthermore, unlike m-AMSA, XK469 did not induce caspase activation or apoptotic cell death in H116 cells. Our results suggest that XK469 is a phase-specific cell cycle inhibitor with a unique mechanism of action that is correlated with the inhibition of cyclin B1 ubiquitination and its accumulation at early M phase. Topics: Amsacrine; Antineoplastic Agents; Apoptosis; Caspases; Cell Cycle; Cell Division; Colonic Neoplasms; Cyclin B; Cyclin B1; Flow Cytometry; Humans; Immunoblotting; Mitosis; Peptide Hydrolases; Quinoxalines; Spindle Apparatus; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Ubiquitin | 2002 |
Painting with a molecular brush: genomic/proteomic interfacing to define the drug action profile of novel solid-tumor selective anticancer agents.
XK469 is an investigational anticancer agent that exhibits antiproliferative activity in tumor-bearing animal models. We examined the drug-action profile of this agent at the molecular level regarding alterations induced in gene expression and proteins in HCT-116 human colon adenocarcinoma cells. We used a unique cDNA microarray (GeneMap(TM) Cancerarray) comprising 1152 human tumor-related genes and 2-D gel electrophoresis, respectively, following a 24-hour exposure to a drug concentration that killed a two-log fraction of HCT-116 clonogenic cells. Functional gene cluster profile (FGCP) analysis of the 71 out of 1152 genes that displayed a >2-fold increase or decrease in expression (over untreated control) identified a drug-specific involvement of the MAPK signal transduction pathway. MAPK signaling together with the involvement of ubiquitin proteins from 2-D gel electrophoresis suggest a novel drug-action profile at the molecular level for the in vitro antiproliferative activity of XK469. Topics: Adenocarcinoma; Antineoplastic Agents; Colonic Neoplasms; Gene Expression Profiling; Humans; MAP Kinase Signaling System; Multigene Family; Neoplasm Proteins; Proteome; Quinoxalines | 2002 |