title: 1082-39, an analogue of sorafenib, inhibited human cancer cell growth more potently than sorafenib.
abstract: OBJECTIVE
  1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells.
  
  
  METHODS
  Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay.
  
  
  RESULTS
  1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways.
  
  
  CONCLUSIONS
  1082-39 is a promising candidate compound which could develop as a potent anticancer agent.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Chu
authors.affiliation: Shandong provincial hospital affiliated to Shandong University, 250021, China.
authors.forename: Cui-Rong
authors.initials: CR
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Song
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Rui-Qi
authors.initials: RQ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Yi-Zhuo
authors.initials: YZ
authors.lastname: Qin
authors.affiliation: Sanlugen PharmaTech, Rm 506, No. 2766 Yingxiu Road, Jinan 250101, China. Electronic address: wbli92128@163.com.
authors.forename: Wen-Bao
authors.initials: WB
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. Electronic address: qxj@sdu.edu.cn.
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Qu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000077157:Sorafenib; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000593491:N-(4-(1-(4-bromoindazole))phenyl)-N'-(4-chloro-3-trifluoromethylphenyl)urea; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases
keywords: 1082-39; Apoptosis; Indazole diarylurea compound; Melanoma cancer cells; Multikinases; Sorafenib