Dun Boying, Xu Heng, Sharma Ashok, Liu Haitao, Yu Hongfang, Yi Bing, Liu Xiaoxin, He Mingfang, Zeng Lingwen, She Jin-Xiong
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.
Int J Clin Exp Pathol. 2013 Nov 15;6(12):2880-6. eCollection 2013.
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.
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.
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.
These results suggest that MPA has beneficial activities for anticancer therapy through diverse molecular pathways and biological processes.
霉酚酸酯（MMF）是霉酚酸（MPA）的前体药物，已广泛用于预防急性移植物排斥反应，它是肌苷单磷酸脱氢酶（IMPDH）的有效抑制剂，IMPDH在许多肿瘤中上调，可能是癌症治疗的靶点。已知MPA可抑制癌细胞增殖并诱导凋亡；然而，其潜在的分子机制仍不清楚。
我们首先通过对13种癌细胞系的体外研究和异种移植模型证明了MPA的抗增殖和促凋亡活性。通过蛋白质印迹分析参与细胞周期、增殖和凋亡的关键蛋白。
对13种癌细胞系的体外处理表明，5种细胞系（AGS、NCI-N87、HCT-8、A2780和BxPC-3）对MPA高度敏感（IC50 < 0.5 μg/ml），4种细胞系（Hs746T、PANC-1、HepG2和MCF-7）对MPA非常耐药（IC50 > 20 μg/ml），另外4种细胞系（KATO III、SNU-1、K562和HeLa）具有中等敏感性。使用胃AGS细胞系的异种移植模型在体内证实了MPA的抗癌活性。使用AGS细胞进行的进一步体外分析表明，MPA可有效诱导细胞周期停滞和凋亡以及抑制细胞增殖。靶向蛋白质组学分析表明，许多导致MPA活性的关键变化发生在蛋白质表达和磷酸化水平。MPA诱导的细胞周期停滞是通过减少许多细胞周期调节因子如CDK4、BUB1、BOP1、Aurora A和FOXM1来实现的。我们还证明MPA可以抑制PI3K/AKT/mTOR途径并诱导半胱天冬酶依赖性凋亡。
这些结果表明，MPA通过多种分子途径和生物学过程对癌症治疗具有有益作用。
