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

Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
British Journal of Pharmacology (Impact Factor: 4.84). 09/2011; 165(6):1813-26. DOI: 10.1111/j.1476-5381.2011.01684.x
Source: PubMed


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.
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.
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.
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.

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    • "UA has been shown to exert many beneficial effects such as anti-diabetes [36], anti-obesity [37], and anti-cancer [38]. Several recent studies show that UA exerts its anti-tumor role through inhibition of the mTOR signaling pathway [39], suggesting a potential mechanism underlying the beneficial effects of UA. "
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    • "Although ursolic acid (UA) was not contained in the selected 200 purified natural compounds, UA is a well-known natural compound belonging to the triterpenoid family and there are many reports regarding the antitumor effects of UA [46–52]. It has also been reported that UA inhibits tumor cell proliferation in several tumor cells, such as breast cancer cells [46], gastric cancer cells [47], colon cancer cells [48], skin cancer cells [49], leukemia cells [50], lung cancer cells [51], and pancreatic cancer cells [52]. Furthermore, it has also been demonstrated that UA suppresses the growth of colon cancer cells by targeting STAT3 [48], whereas the effects of UA on macrophage activation are unknown. "
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