Impact on Glioblastoma U87 Cell Gene Expression of a Carborane Cluster-Bearing Amino Acid: Implications for Carborane Toxicity in Mammalian Cells

Carboranes have been extensively investigated as potential drugs for the treatment of malignant human brain tumors by boron neutron capture therapy (BNCT). This noninvasive treatment modality utilizes compounds containing the nonradioactive isotope B-10 which has a high propensity to capture slow neutrons. In response, it emits high energy alpha-particles that kill the cell. We have successfully synthesized a boron delivery agent by installing a boron-rich m-carborane within the amino acid cysteine. Rapid uptake of this compound into U87 glioblastoma cells within 5 min of exposure was observed, and fluorescence microscopy studies showed that it was retained intracellularly after 48 h. In the absence of thermal neutrons, a cytostatic effect in U87 cells was observed at exposures ranging from 1 mu M to 1 mM relative to the control, while no change was observed at 1-0.01 mu M. Microarray studies unveiled a wide range of unique changes in the gene expression profile of the U87 cells, particularly for the genes associated with cell cycle, which were observed to be greatly suppressed after treatment with the compound. These results were validated by qPCR studies. Although the compound was designed for BNCT, its distinctive impacts on gene regulation reveal that it and other carborane-containing cluster molecules may exert unique heretofore unknown effects on the transcriptome, even in the absence of applied radiation.