title: Micheliolide derivative DMAMCL inhibits glioma cell growth in vitro and in vivo.
abstract: BACKGROUND
  There is no highly effective chemotherapy for malignant gliomas to date. We found that dimethylaminomicheliolide (DMAMCL), a selective inhibitor of acute myeloid leukemia (AML) stem/progenitor cells, inhibited the growth of glioma cells.
  
  
  METHODS
  The distribution of DMAMCL in brain was analyzed by an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) system. The anti-tumor evaluations of DMAMCL in vitro were performed by MTT, FACS and RT-PCR. In vivo, the mixture of C6 cells and matrigel was injected into caudatum, and the anti-tumor activity of DMAMCL was evaluated by tumor growth and rat survival. The toxicity of DMAMCL was evaluated by body weight, daily food intake, hematological or serum biochemical analyses, and histological appearance of tissues.
  
  
  RESULTS
  The IC50 values of DMAMCL against the C6 and U-87MG cell lines in vitro were 27.18 ± 1.89 μM and 20.58 ± 1.61 μM, respectively. DAMMCL down-regulated the anti-apoptosis gene Bcl-2 and increased apoptosis in C6 and U-87MG cells in a dose-dependent manner. In a C6 rat tumor model, daily administration of DMAMCL for 21 days reduced the burden of C6 tumors by 60% to 88% compared to controls, and more than doubled the mean lifespan of tumor-bearing rats. Distribution analysis showed that the DMAMCL concentration was higher in the brain than in plasma. Evaluations for toxicity revealed that oral administration of DMAMCL at 200 or 300 mg/kg once a day for 21 days did not result in toxicity.
  
  
  CONCLUSIONS
  These results suggest that DMAMCL is highly promising for the treatment of glioma.
authors: Clinical Laboratory Center, Chinese PLA Air Force General Hospital, Haidian, Beijing 100142, PR China.
authors: Yinghong
authors: Y
authors: An
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors: Wanjun
authors: W
authors: Guo
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors: Linna
authors: L
authors: Li
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors: Chengwang
authors: C
authors: Xu
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors: Dexuan
authors: D
authors: Yang
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors: Shanshan
authors: S
authors: Wang
authors: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors: Yaxin
authors: Y
authors: Lu
authors: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors: Quan
authors: Q
authors: Zhang
authors: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors: Jiadai
authors: J
authors: Zhai
authors: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors: Hongxia
authors: H
authors: Fan
authors: Accendatech Co., Ltd., Tianjin 300384, PR China.
authors: Chuanjiang
authors: C
authors: Qiu
authors: Accendatech Co., Ltd., Tianjin 300384, PR China.
authors: Jie
authors: J
authors: Qi
authors: Accendatech Co., Ltd., Tianjin 300384, PR China.
authors: Yue
authors: Y
authors: Chen
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors: Shoujun
authors: S
authors: Yuan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy / Q000503:physiopathology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045789:Sesquiterpenes, Guaiane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D045789:Sesquiterpenes, Guaiane; D013778:Tetrazolium Salts; D013844:Thiazoles; C577929:dimethylaminomicheliolide; C022616:thiazolyl blue