Suppression of hepatocellular carcinoma by mycophenolic acid in experimental models and in patients

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. A LT database was used for retrospective analysis of the effect of mycophenolate mofetil (MMF), the prodrug of MPA, on HCC recurrence. Results: With clinically achievable concentrations, MPA effectively inhibited HCC cell proliferation and single cell colony formation unit (CFU). 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 MMF 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. # These authors contribute equally Conflicts of interest: The authors declare no conflict of interest. Funding: 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 (ZSTU) under Grant (No. 17042057-Y); Ministry of Science and Technology Assistance Project Grant (No. KY201501005). Acknowledgment: We thank the Center for Drug Design, University of Minnesota, Minneapolis, USA, for supporting the development of the IMPDH inhibitors. Author Contributions: K.C was responsible for acquisition of data, analysis and interpretation of data and drafting of the manuscript; 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.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 manuscript; M.P was involved in analysis and interpretation of data, study supervision and critical revision of the manuscript; Q.P was responsible for study concept and design, analysis and interpretation of data, funding obtain, study supervision and critical revision of the manuscript. *To whom correspondence should be addressed: Qiuwei Pan, Department of Gastroenterology and Hepatology, Erasmus MC, room Na-1005, 'sGravendijkwal 230, NL-3015 CE Rotterdam, The Netherlands, Phone: +31(0)107037502, Fax: +31-(0)107032793. E-mail: q.pan@erasmusmc.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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