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Suppression of Hepatocellular Carcinoma by Mycophenolic Acid in Experimental Models and in Patients

Chen, Kan1,2,3; Sheng, Jiexin4; Ma, Buyun3; Cao, Wanlu3; Hernanda, Pratika Y.3,5; Liu, Jiaye3; Boor, Patrick P.C.3; Tjon, Angela S.W.3; Felczak, KrzysztofPhD,6; Sprengers, Dave3; Pankiewicz, Krzysztof W.6; Metselaar, Herold J.3; Ma, Zhongren1; Kwekkeboom, Jaap3; Peppelenbosch, Maikel P.3; Pan, Qiuwei, PhD1,3

doi: 10.1097/TP.0000000000002647
Original Basic Science—Liver
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Background. Tumor recurrence is a major complication following liver transplantation (LT) as treatment for hepatocellular carcinoma (HCC). Immunosuppression is an important risk factor for HCC recurrence, but conceivably may depend on the type of immunosuppressive medication. Mycophenolic acid (MPA) is a currently widely used immunosuppressant. This study investigated the effects of MPA on HCC.

Methods. Three human HCC cell lines and organoids from mouse primary liver tumor were used as experimental models. MTT, Alamar Blue assay, cell cycle analysis, colony formation, and [3H]-thymidine assays were performed. An LT database was used for retrospective analysis of the effect of mycophenolate mofetil, the prodrug of MPA, on HCC recurrence.

Results. With clinically achievable concentrations, MPA effectively inhibited HCC cell proliferation and single-cell colony-forming unit. In short-term experiments, MPA effectively elicited S phase arrest in HCC cell lines. In addition, the initiation and growth of liver tumor organoids were effectively inhibited by MPA. Most importantly, the use of mycophenolate mofetil in patients with HCC-related LT was significantly associated with less tumor recurrence and improved patient survival.

Conclusions. MPA can specifically counteract HCC growth in vitro and tumor recurrence in LT patients. These results warrant prospective clinical trials into the role of MPA-mediated immunosuppression following LT of patients with HCC.

1 Biomedical Research Center, Northwest Minzu University, Lanzhou, China.

2 College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.

3 Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.

4 Department of Medical Diagnostic Imageology, Hanzhong Central Hospital, Hanzhong, Shaanxi, China.

5 Laboratory of Medical Genetics, Biomolecular Research Center, Wijaya Kusuma University, Surabaya, Indonesia.

6 Center for Drug Design, University of Minnesota, Minneapolis, MN.

Received 30 August 2018. Revision received 28 December 2018.

Accepted 1 January 2019.

K.C. and J.S. contributed equally to this work.

The authors declare no conflicts of interest.

This work was supported by the Central Universities deriving from the Northwest Minzu University (No. 31920180124), Zhejiang Provincial Natural Science Foundation of China (No. LY18H160066), Science Foundation of Zhejiang Sci-Tech University (grant 17042057-Y), and Ministry of Science and Technology Assistance Project (grant KY201501005).

K.C. was responsible for acquisition of data, analysis and interpretation of data, and drafting of the article. J.S., B.M., J.L., and P.P.C.B. performed experiments and data analysis. P.Y.H., D.S., and A.S.W.T. collected clinical information and performed analysis. K.F. and K.W.P. were involved in compound design and synthesis. Z.M., J.K., and H.J.M. were involved in discussing the project, interpretation of data, and critical revision of the article. M.P.P. was involved in analysis and interpretation of data, study supervision, and critical revision of the article. Q.P. was responsible for study concept and design, analysis and interpretation of data, obtaining funding, study supervision, and critical revision of the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Qiuwei Pan, PhD, Department of Gastroenterology and Hepatology, Erasmus MC, Room Na-1005, ‘sGravendijkwal 230, NL-3015 CE, Rotterdam, The Netherlands. (q.pan@erasmusmc.nl)

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