Pharmaprojects R&D Pipeline News Feed
PPARγ : A new avenue for cancer therapeutics?
19th Feb 2007
Researchers from the University of Rochester Medical Center in New York have inadvertently stumbled across a potential new treatment for colorectal cancer.
Dr Katherine Schaefer and her team were investigating whether peroxisome proliferator-activated receptor-gamma (PPARγ) modulators could be used as anti-inflammatories in Crohn's disease and ulcerative colitis, using colorectal cancer cells, because unlike healthy gut cells, they can live on when they are removed from the gut wall.
Whilst comparing PPARγ activators and inhibitors in this system, the team noticed that their experimental cancer cells were dying before the tests were concluded, indicating a potential anticancer role for PPARγ modulators. Indeed, further experiments revealed that the PPARγ inhibitors T-0070907, GW-9662 and bisphenol A diglycidyl ether (BADGE) interfered with cancerous cell growth and metastasis, and also stimulated apoptosis. The compounds also reduced tubulin levels in cancer cells by 60-70%, exhibiting the same mechanism of action as the blockbuster chemotherapeutic Taxol (paclitaxel) which had peak annual sales of US$1.6 billion in 2000.
Until now, paclitaxel-based therapies have failed in colorectal cancer trials due to the presence of 'efflux' proteins which pump the drug out of the cell. Paclitaxel-resistance also develops in almost 100% of breast and lung cancers due to mutations in the drug binding site. It seems that PPARγ inhibitors may circumvent these problems by inhibiting tubulin, but escaping the effect of efflux proteins and binding to a different tubulin-binding site.
PPARγ inhibitors have already shown antitumour activity in murine models without causing significant toxicity, and more formal studies of these promising compounds are underway.
