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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3441-3450.
Prepublished online as a Blood First Edition Paper on December 29, 2006; DOI 10.1182/blood-2006-06-032250.
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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-Juan 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{at}stn.sh.cn.
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.
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