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J Cachexia Sarcopenia Muscle. Dec 2012; 3(4): 277–278.
Published online Nov 13, 2012. doi:  10.1007/s13539-012-0091-5
PMCID: PMC3505581
Ursodeoxycholic acid and its emerging role in attenuation of tumor growth in gastrointestinal malignancies
Shailendra Kapoorcorresponding author
University of Illinois at Chicago, Chicago, IL USA
Shailendra Kapoor, Phone: +1-865-6071014, Fax: +1-865-6786787, shailendrakapoor/at/yahoo.com.
corresponding authorCorresponding author.
Received October 17, 2012; Accepted October 25, 2012.
Dear Editor,
I read with great interest the recent article by Tschirner et al. [1]. 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 [2]. Interestingly, UDCA decreases the odds of advanced lesions in males only [3]. Similarly, UDCA downregulates c-Myc expression [4]. 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 [5]. 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 [6].
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 [7]. 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 [8]. Apoptosis secondary to UDCA is attenuated by U0126 as well as by PD98059.
Similarly, DLC1 degradation by proteosomes is attenuated by UDCA [9]. 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 [10]. 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 [11].
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.
Acknowledgment
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.
Footnotes
A reply to this comment can be found at doi 10.1007/s13539-012-0092-4.
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;3:31–36. doi: 10.1007/s13539-011-0044-4. [PMC free article] [PubMed] [Cross Ref]
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. 2012;318:819–827. doi: 10.1016/j.yexcr.2012.02.004. [PubMed] [Cross Ref]
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;2:1023–1030. doi: 10.1158/1940-6207.CAPR-09-0234. [PubMed] [Cross Ref]
4. Peiro-Jordan R, 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. 2012;21:413–422. doi: 10.1097/CEJ.0b013e32834ef16f. [PubMed] [Cross Ref]
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. doi: 10.1080/01635580701883003. [PubMed] [Cross Ref]
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;29:4971–4979. [PubMed]
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;28:1429–1434. [PubMed]
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. Carcinogenesis. 2011;32:723–731. doi: 10.1093/carcin/bgr038. [PubMed] [Cross Ref]
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;25:1739–1746. [PubMed]
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. 2010;126:1582–1595. [PubMed]
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;19:487–491. doi: 10.1097/MEG.0b013e3281108068. [PubMed] [Cross Ref]
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