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

Boying Dun, Heng Xu, Ashok Kumar Sharma, Haitao Liu, Hongfang Yu, Bing Yi, Xiaoxin Liu, Mingfang He, Lingwen Zeng, Jin-Xiong She

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2880-2886
Number of pages7
JournalInternational Journal of Clinical and Experimental Pathology
Volume6
Issue number12
Publication statusPublished - Dec 5 2013

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Keywords

  • Apoptosis
  • Cancer
  • Drug repurposing
  • Mpa
  • Xenograft

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

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