Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells
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Qing Ji1,*, Ya-hui Ding1,2,*, Yue Sun1,*, Yu Zhang1,*, Hui-er Gao1, He-nan Song1, Ming Yang1, Xiao-lei Liu1, Zi-xiang Zhang3, Ying-hui Li1, Ying-dai Gao1
1State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
2The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
3Department of Stomatology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China
*These authors contributed equally to this work
Ying-dai Gao, email: email@example.com
Keywords: leukemic stem cells, micheliolide
Received: February 24, 2016 Accepted: August 09, 2016 Published: August 17, 2016
Leukemic stem cells (LSCs) greatly contribute to the initiation, relapse, and multidrug resistance of leukemia. Current therapies targeting the cell cycle and rapidly growing leukemic cells, including conventional chemotherapy, have little effect due to the self-renewal and differentiated malignant cells replenishment ability of LSCs despite their scarce supply in the bone marrow. Micheliolide (MCL) is a natural guaianolide sesquiterpene lactone (GSL) which was discovered in michelia compressa and michelia champaca plants, and has been shown to exert selective cytotoxic effects on CD34+CD38− LSCs. In this study, we demonstrate that DMAMCL significantly prolongs the lifespan of a mouse model of human acute myelogenous leukemia (AML). Mechanistic investigations further revealed that MCL exerted its cytotoxic effects via inhibition of NF-κB expression and activity, and by generating intracellular reactive oxygen species (ROS). These results provide valuable insight into the mechanisms underlying MCL-induced cytotoxicity of LSCs, and support further preclinical investigations of MCL-related therapies for the treatment of AML.
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