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.
|1.||Tschirner A, von Haehling S, Palus S, Doehner W, Anker SD, Springer J. Ursodeoxycholic acid treatment in a rat model of cancer
cachexia. J Cachexia Sarcopenia Muscle. 2012;3:31–6. doi:10.1007/s13539-011-0044-4.
|2.||van Heumen BW, Roelofs HM, Te
Morsche RH, Marian B, Nagengast FM, Peters WH. Celecoxib and
tauro-ursodeoxycholic acid co-treatment
inhibits cell growth in familial adenomatous
polyposis derived LT97 colon adenoma cells. Exp Cell Res.
|3.||Thompson PA, Wertheim BC, Roe DJ, et al. Gender modifies the effect of ursodeoxycholic acid in a randomized controlled trial
in colorectal adenoma patients. Cancer Prev Res (Phila). 2009;2:1023–30.
Krishna-Subramanian S, Hanski ML, Luscher-Firzlaff J, Zeitz M, Hanski C.
The chemopreventive agent ursodeoxycholic
acid inhibits proliferation of colon carcinoma
cells by suppressing c-Myc expression. Eur J Cancer Prev.
|5.||Khare S, Mustafi R, Cerda S, et al. Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and
CCAAT/enhancer-binding protein. Nutr Cancer. 2008;60:389–400.
|6.||Asciutti S, Castellani D, Nardi E, et al. A new amino acid derivative of ursodeoxycholate, (N-L-glutamyl)-UDCA (UDCA-Glu),
to selectively release UDCA in the colon. Anticancer Res. 2009;29:4971–9.
|7.||Lim SC, Duong HQ, Parajuli KR, Han SI. Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis
in SNU601 gastric cancer cells. Oncol Rep. 2012;28:1429–34.
|8.||Lim SC, Duong HQ, Choi JE, et
al. Lipid raft-dependent death receptor 5 (DR5) expression and
activation are critical for ursodeoxycholic
acid-induced apoptosis in gastric cancer cells.
|9.||Chung GE, Yoon JH, Lee JH, et al. Ursodeoxycholic acid-induced inhibition of DLC1 protein degradation leads to suppression
of hepatocellular carcinoma cell growth. Oncol Rep. 2011;25:1739–46.
|10.||Lim SC, Choi JE, Kang HS, Han
SI. Ursodeoxycholic acid switches oxaliplatin-induced necrosis to
apoptosis by inhibiting reactive
oxygen species production and activating
p53-caspase 8 pathway in HepG2 hepatocellular carcinoma. Int J Cancer.
|11.||Rudolph G, Kloeters-Plachky P, Rost D, Stiehl A. The incidence of cholangiocarcinoma in primary sclerosing cholangitis after
long-time treatment with ursodeoxycholic acid. Eur J Gastroenterol Hepatol. 2007;19:487–91.