Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo

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BlankBlood First Edition Paper, prepublished online December 29, 2006; DOI

10.1182/blood-2006-06-032250.

Submitted June 30, 2006

Accepted December 4, 2006

Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion

protein and shows potent antitumor activity with low adverse effects on t(8;21)

leukemia in vitro and in vivo

Guang-Biao Zhou, Hui Kang, Lan Wang, Li Gao, Ping Liu, Jun Xie, Feng-Xiang

Zhang, Xiang-Qin Weng, Zhi-Xiang Shen, Jue Chen, Long-Jun Gu, Ming Yan, Dong-Er

Zhang, Sai- Chen, Zhen-Yi Wang, and Zhu Chen*

State Key Laboratory of Medical Genomics, & Shanghai Institute of Hematology,

Rui Jin Hospital, Shanghai Jiao Tong University School of Med., Shanghai, China

Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences,

Guangzhou, China

Children' Medical Center, Medical School Shanghai Jiao Tong University,

Shanghai, China

Department of Molecular and Experimental Medicine, The Scripps Research

Institute, La Jolla, CA, United States

Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University,

Shanghai, China

* Corresponding author; email: zchen@... .

Studies have documented the potential antitumor activities of oridonin, a

compound extracted from medicinal herbs. However, whether oridonin can be used

in selected setting of hematology/oncology remains obscure. Here we reported

that oridonin induced apoptosis of t(8;21) acute myeloid leukemic (AML) cells.

Intriguingly, the t(8;21) product, AML1-ETO (AE) fusion protein which plays a

critical role in leukemogenesis, was degraded with generation of a catabolic

fragment, while the expression pattern of AE target genes investigated could be

reprogrammed. The ectopic expression of AE enhanced the apoptotic effect of

oridonin in U937 cells. Pre-incubation with caspases inhibitors blocked

oridonin-triggered cleavage of AE, while substitution of Ala for Asp at residues

188 in ETO moiety of the fusion abrogated AE degradation. Furthermore, oridonin

prolonged life-span of C57 mice bearing truncated AE-expressing leukemic cells

without suppression of bone marrow or reduction of body weight of animals, and

exerted synergic effects while combined with cytosine arabinoside. Oridonin also

inhibited tumor growth in nude mice inoculated with t(8;21)-harboring Kasumi-1

cells. These results suggest that oridonin may be a potential anti-leukemia

agent which targets AE oncoprotein at residue D188 with low adverse effect, and

may be helpful for the treatment of patients with t(8; 21) AML.