title: Ursolic acid induces apoptosis in human leukaemia cells and exhibits anti-leukaemic activity in nude mice through the PKB pathway.
abstract: OBJECTIVE
  Ursolic acid (UA) has been extensively used as an anti-leukaemic agent in traditional Chinese medicine. In the present study, we investigated the ability of UA to induce apoptosis in human leukaemia cells in relation to its effects on caspase activation, Mcl-1 down-regulation and perturbations in stress-induced signalling pathways such as PKB and JNK.
  
  
  METHODS
  Leukaemia cells were treated with UA after which apoptosis, caspase activation, PKB and JNK signalling pathways were evaluated. The anti-tumour activity of UA was evaluated using xenograft mouse model.
  
  
  RESULTS
  UA induced apoptosis in human leukaemia cells in a dose- and time-dependent manner; this was associated with caspase activation, down-regulation of Mcl-1 and inactivation of PKB accompanied by activation of JNK. Enforced activation of PKB by a constitutively active PKB construct prevented UA-mediated JNK activation, Mcl-1 down-regulation, caspase activation and apoptosis. Conversely, UA lethality was potentiated by the PI3-kinase inhibitor LY294002. Interruption of the JNK pathway by pharmacological or genetic (e.g. siRNA) attenuated UA-induced apoptosis. Furthermore, UA-mediated inhibition of tumour growth in vivo was associated with induction of apoptosis, inactivation of PKB as well as activation of JNK.
  
  
  CONCLUSIONS
  Collectively, these findings suggest a hierarchical model of UA-induced apoptosis in human leukaemia cells in which UA induces PKB inactivation, leading to JNK activation and culminating in Mcl-1 down-regulation, caspase activation and apoptosis. These findings indicate that interruption of PKB/JNK pathways may represent a novel therapeutic strategy in haematological malignancies.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Senping
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Jieping
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: E-Hu
authors.initials: EH
authors.lastname: Liu
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Deying
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Zailin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, ChinaGraduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KentuckyDepartment of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, ChinaKey Laboratory of Modern Chinese Medicines (China Pharmaceutical University), Ministry of Education, Nanjing, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014315:Triterpenes / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000097245:Ursolic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020169:Caspases; D048670:MAP Kinase Kinase 4; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; D000097245:Ursolic Acid; C579094:Mcl1 protein, mouse; C499321:Parp1 protein, mouse