Original Article Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid

Background: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA) which has been wide- ly 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 can- cer 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 (IC 50 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 ar- rest 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.