title: Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid.
abstract: BACKGROUND
  Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA) which has been widely used for the prevention of acute graft rejection, is a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and potentially a target for cancer therapy. MPA is known to inhibit cancer cell proliferation and induces apoptosis; however, the underlying molecular mechanisms remain elusive.
  
  
  METHODS
  We first demonstrated MPA's antiproliferative and proapoptotic activities using in vitro studies of 13 cancer cell lines and a xenograft model. Key proteins involved in cell cycle, proliferation and apoptosis were analyzed by Western blotting.
  
  
  RESULTS
  In vitro treatment of thirteen cancer cell lines indicated that five cell lines (AGS, NCI-N87, HCT-8, A2780 and BxPC-3) are highly sensitive to MPA (IC50 < 0.5 μg/ml), four cell lines (Hs746T, PANC-1, HepG2 and MCF-7) are very resistant to MPA (IC50 > 20 μg/ml) and the four other cell lines (KATO III, SNU-1, K562 and HeLa) have intermediate sensitivity. The anticancer activity of MPA was confirmed in vivo using xenograft model with gastric AGS cell line. Further in vitro analyses using AGS cells indicated that MPA can potently induce cell cycle arrest and apoptosis as well as inhibition of cell proliferation. Targeted proteomic analyses indicate that many critical changes responsible for MPA's activities occur at the protein expression and phosphorylation levels. MPA-induced cell cycle arrest is achieved through reduction of many cell cycle regulators such as CDK4, BUB1, BOP1, Aurora A and FOXM1. We also demonstrate that MPA can inhibit the PI3K/AKT/mTOR pathway and can induce caspase-dependent apoptosis.
  
  
  CONCLUSIONS
  These results suggest that MPA has beneficial activities for anticancer therapy through diverse molecular pathways and biological processes.
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences 190 Kaiyuan Road, Guangzhou 510530, China ; Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University 1120 15th Street, Augusta, GA 30912, USA ; Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology Nanjing, China.
authors.forename: Boying
authors.initials: B
authors.lastname: Dun
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
authors.forename: Haitao
authors.initials: H
authors.lastname: Liu
authors.forename: Hongfang
authors.initials: H
authors.lastname: Yu
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Liu
authors.forename: Mingfang
authors.initials: M
authors.lastname: He
authors.forename: Lingwen
authors.initials: L
authors.lastname: Zeng
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009173:Mycophenolic Acid / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid
keywords: MPA; apoptosis; cancer; drug repurposing; xenograft