Ursodeoxycholic acid and its emerging role in attenuation of tumor growth in gastrointestinal malignancies
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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.
The author of this manuscript certifies that he complies with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (von Haehling S, Morley JE, Coats AJ, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle. 2010;1:7–8.)
Conflict of interest
The author has no conflicts of interest.