Urso as Chemopreventative
Off-label therapeutic inspirations sometimes come from my patients.
And this one came from Noreen T. Noreen has advanced metastatic breast cancer refractory to almost all treatments and has just started on an investigational Dendritic vaccine + Zadaxin (thymosin) but her disease is progressing rapidly with rising markers and an obstructive jaundice caused by liver metastases. External drainage and internal stenting was out of the question and she was offered lactulose as we need to buy time for the immune treatments to work. In my searches, I came across Ursodiol (Urso) which I am familiar with in its use in preventing gallstones or for primary biliary cirrhosis and other cholestatic conditions. Its just that its not usually used in oncology. Researching deeper led to the interesting discovery for me that it is also an anti-cancer (which I doubt that most my hepatology or GI colleagues are aware). Even more interesting was a converse (vis-a-vis this blog) discovery, that Tamoxifen which is traditionally used for breast cancer, may be useful as an off-label treatment for primary biliary cirrhosis (Reddy et al. Liver Int., 2004 Jun;24(3):194-7)! So thank you Noreen for leading me to a treasure trove of discoveries!
What is Urso?
Ursodiol or Ursodeoxycholic (Actigall, URSO) is a naturally derived bile acid that decreases the amount of cholesterol produced by the liver and absorbed by the intestines. Interestingly, ursodiol is found in large quantities and the major therapeutic ingredient in bear bile, which is an established if controverial member of traditional Chinese medicine’s pharmacopoeia. Ursodiol helps break down cholesterol that has formed into stones in the gallbladder and is also hepatoprotective. Ursodiol also increases bile flow, which is why it is useful in cholestatic conditions such as biliary cirrhosis. Since the 1980’s, Urso has been in widespread clinical use for biliary conditions. But what surprised me when researching the potential application of Urso for Noreen’s case is the anti-cancer properties of Urso.
Urso and Cancer
Earnest DL et al. from the U. of Arizona reported as early as 1994 that Urso is a potential chemopreventative agent in experimental colon cancer and highlighted a role of bile salts in modulating gastrointestinal cancer development, and it wasn’t long before Urso became a recognized chemopreventative agent against colon cancer in those with inflammatory bowel disease (See Itzkowitz SH, Gastroenterol Clin North Am. 2002 Dec;31(4):1133-44). In 1997, the Korean team Park YH et al. reported that Urso induced apoptosis (suicide) of liver cancer cells in vitro (Arch Pharm Res. 1997 Feb;20(1):29-33) and the same team further demonstrated derivatives of Urso had efficacy against prostate and breast cancers in later studies. Im and Martinez more recently demonstrated that Urso induced apoptosis in colon cancer partly via modulation of EGFR/Raf-1/ERK signaling (Nutr Cancer. 2005;51(1):110-6.) A most recent review of Urso as an apoptotic is found in a review by Amaral JD et al. in J Lipid Res. 2009 May 5.
Granted, clinical data for Urso as a cancer treatment is not available and its main potential seems to be the use as chemopreventative in those at high risk for colon or liver cancers to reduce the risk, but attempts to synthesize Urso and other bile salt derivatives for cancer treatment is already on the way.