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

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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
StatePublished - Dec 5 2013

Fingerprint

Mycophenolic Acid
Cell Line
Apoptosis
Cell Proliferation
Neoplasms
Cell Cycle Checkpoints
Heterografts
Cell Cycle
Biological Phenomena
Inosine Monophosphate
Prodrugs
Graft Rejection
Caspases
Phosphatidylinositol 3-Kinases
Proteomics
Inhibitory Concentration 50
Stomach
Oxidoreductases
Proteins
Western Blotting

Keywords

  • Apoptosis
  • Cancer
  • Drug repurposing
  • Mpa
  • Xenograft

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

Cite this

Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid. / Dun, Boying; Xu, Heng; Sharma, Ashok Kumar; Liu, Haitao; Yu, Hongfang; Yi, Bing; Liu, Xiaoxin; He, Mingfang; Zeng, Lingwen; She, Jin-Xiong.

In: International Journal of Clinical and Experimental Pathology, Vol. 6, No. 12, 05.12.2013, p. 2880-2886.

Research output: Contribution to journalArticle

Dun, Boying ; Xu, Heng ; Sharma, Ashok Kumar ; Liu, Haitao ; Yu, Hongfang ; Yi, Bing ; Liu, Xiaoxin ; He, Mingfang ; Zeng, Lingwen ; She, Jin-Xiong. / Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid. In: International Journal of Clinical and Experimental Pathology. 2013 ; Vol. 6, No. 12. pp. 2880-2886.
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T1 - Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid

AU - Dun, Boying

AU - Xu, Heng

AU - Sharma, Ashok Kumar

AU - Liu, Haitao

AU - Yu, Hongfang

AU - Yi, Bing

AU - Liu, Xiaoxin

AU - He, Mingfang

AU - Zeng, Lingwen

AU - She, Jin-Xiong

PY - 2013/12/5

Y1 - 2013/12/5

N2 - 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.

AB - 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.

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KW - Cancer

KW - Drug repurposing

KW - Mpa

KW - Xenograft

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