Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells.

Abstract

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.

• Authors: Qing Ji, Ya-Hui Ding, Yue Sun, Yu Zhang, Hui-Er Gao, He-Nan Song, Ming Yang, Xiao-Lei Liu, Zi-Xiang Zhang, Ying-Hui Li, Ying-Dai Gao
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 40 Pg. 65012-65023 (Oct 04 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27542251 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• NF-kappa B
• Reactive Oxygen Species
• Sesquiterpenes, Guaiane
• micheliolide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Self Renewal (drug effects)
• Disease Models, Animal
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Magnoliaceae (immunology)
• Mice
• Mice, SCID
• NF-kappa B (metabolism)
• Neoplastic Stem Cells (drug effects, physiology)
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes, Guaiane (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays