I read with great interest the recent article by Tschirner et al. . Interestingly, recent data suggest that ursodeoxycholic acid (UDCA) may attenuate tumor growth in a number of gastrointestinal malignancies.
For instance, tauro-ursodeoxycholic acid when administered along with celecoxib attenuates proliferation and tumor growth in colonic adenomas . Interestingly, UDCA decreases the odds of advanced lesions in males only . Similarly, UDCA downregulates c-Myc expression . As a result, it attenuates tumor growth in colon carcinomas. CDK6 expression is also decreased secondary to UDCA administration. UDCA downregulates Cox-2 also, thus further inhibiting tumor growth. It also attenuates CCAAT/enhancer binding protein beta (C/EBPbeta) at the same time . It also effects p38 and Ras expression and thereby further modulates Cox-2 function. Recently, UDCA conjugates with glutamic acid have been developed that result in enhanced intraluminal delivery of UDCA inside the colon .
Similarly, UDCA inhibits gastric carcinogenesis. It does this by modulating the MEK/ERK pathway. It accentuates MEK1/2 phosphorylation as well as ERK1/2 phosphorylation . DR 5 receptors are necessary for UDCA-mediated apoptosis. Modulation of the raft formation/ROS production/PKCδ activation pathway can effect UDCA-mediated apoptosis as it in turn effects and controls DR5 expression . Apoptosis secondary to UDCA is attenuated by U0126 as well as by PD98059.
Similarly, DLC1 degradation by proteosomes is attenuated by UDCA . Subsequently, there is decreased proliferation and growth in hepatocellular carcinomas. UDCA administration is simultaneously accompanied by a decrease in RhoA activity. Similarly, UDCA upregulates Bax expression and downregulates Bcl-2 expression. Interestingly, the p53-caspase 8 pathway is activated by UDCA which mediates the conversion from oxaliplatin-induced necrosis to apoptosis in hepatocellular carcinomas . At the same time, UDCA inhibits ROS production. Hence, combination therapy in hepatocellular carcinomas may benefit from the addition of UDCA. Similarly, UDCA has a negative impact on the incidence rate of cholangiocarcinomas in patients with primary sclerosing cholangitis .
It is clearly evident from the above examples that UDCA can play a major role in attenuating carcinogenesis in the gastrointestinal tract. There is a clear and urgent need for further studies in this regard.