Inventor: Barrie P. Bode, Ph.D.
In liver diseases including hepatocellular carcinoma (HCC) and cirrhosis there is a net increase in glutamine consumption that subverts the systemic glutamine homeostatic function of the liver and results in reduced plasma glutamine levels that can adversely impact the glutamine-dependent cells of the immune system. HCC cells take up glutamine at rates 10 to 30-fold faster than normal hepatocytes.
A cDNA has been isolated that encodes for a broad specificity Na+-dependent glutamine transporter referred to as "ATB0". The properties of ATB0 match those reported for the System ASC-like hepatoma activity that is reported to govern glutamine-dependent growth in SK-Hep human hepatoma cells. Specific down-regulation of ATB0 activity in hepatoma cells culminates in death of the hepatoma cells by apoptosis.
Agents useful for inhibiting ATB0 activity include antibodies against ATB0, siRNAs that target ATB0 RNA for destruction, and, various ATB0 inhibitory small molecules such as amino acid analogs that block uptake of glutamine through the ATB0 transporter, anti-sense polynucleotides that block production of active ATB0 and, ribozymes that specifically destroy ATB0 RNAs. Moreover, agents such as antibodies specific for ATB0 may be useful tools in diagnosing human liver cancer clinically.
Application: Treatment of liver disease
Keywords: Hepatocellular carcinoma, glutamine, hepatoma
Patent: PCT/US04/21101 (filed: June 30, 2004)
Reference Number: SLU-1025