Ursolic acid induces apoptosis in human leukaemia cells and exhibits anti-leukaemic activity in nude mice through the PKB pathway

Ning Gao, Senping Cheng, Amit Budhraja, Ziyi Gao, Jieping Chen, E. Hu Liu, Cheng Huang, Deying Chen, Zailin Yang, Qun Liu, Ping Li, Xianglin Shi, Zhuo Zhang

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Background and purpose: 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. Experimental approach: 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. Key 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 and implications: 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.

Original languageEnglish
Pages (from-to)1813-1826
Number of pages14
JournalBritish Journal of Pharmacology
Volume165
Issue number6
DOIs
StatePublished - Mar 2012

Keywords

  • PKB
  • apoptosis
  • leukaemia
  • ursolic acid
  • xenograft

ASJC Scopus subject areas

  • Pharmacology

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