micheliolide and Leukemia

Natural products are important leads in drug discovery. In recent years, the anti-leukemic properties of natural compounds isolated from plants, containing an α-Methylene-γ-lactones skeleton, have attracted a lot of attention. Extensive research has been carried out to characterize their molecular mechanisms of action and potential chemotherapeutic application in different types of cancer, including leukemias. Sesquiterpene lactones, a group of α-Methylene-γ-lactones are plant-derived compounds, mostly of the Compositae family, used in traditional medicine especially for the treatment of inflammation. However, they exhibit a broad spectrum of other biological effects, including cytotoxic, anti-bacterial, anti-helminthic, and anti-tumor activity. Recently, a sesquiterpene lactone, parthenolide, and several other compounds containing an α-methylene-γ-lactone skeleton have become topics of interest as potential antileukemic agents. The recent research emphasizes their selective activity against leukemia cells while the normal hematopoietic cells remain unaffected. In this review, we give a brief description of natural α-Methylene-γ-lactones isolated from plants and their derivates with minor chemical modifications that possess anti-leukemic activity. We also discuss molecular mechanisms of action of these compounds, in particular, their selectivity against leukemia cells.

Topics: Animals; Antineoplastic Agents; Humans; Lactones; Leukemia; Neoplastic Stem Cells; Plant Extracts; Sesquiterpenes; Sesquiterpenes, Guaiane

Accumulating evidence has supported that targeting oxidative stress and metabolic alterations of cancer is an effective strategy to combat cancer. We previously reported that Dimethylaminomicheliolide (DMAMCL) and its active metabolite micheliolide (MCL) can cause oxidative stress and cell death in leukemia and glioblastoma. However, the detailed mechanism underlying MCL or DMAMCL triggered oxidative stress remains elusive. Herein, using leukemia HL60 cells and glioblastoma U118MG cells as models, we found that MCL-induced oxidative stress is mainly mediated by reduced glutathione (GSH). Overproduced reactive oxygen species (ROS) can lead to oxidative damage to mitochondrial, impairing the ability of the tricarboxylic acid (TCA) cycle and causing dysfunction of mitochondrial respiratory chain. On the other hand, the depletion of GSH activates GSH biosynthesis pathway and has possibility to give rise to more GSH to scavenge ROS in cancer cells. Targeting this redox and metabolic circuit, we identified L-buthionine sulfoximine (BSO), an inhibitor in GSH biosynthesis, as an agent that can enhance MCL regimen to inhibit GSH compensatory event and thereby further facilitate cancer cell oxidative stress. Together, these results illustrate that targeting redox and metabolic pathway by MCL/DMAMCL combination with BSO is a potent therapeutic intervention for the treatments of glioblastoma and acute-myelocytic leukemia.

Topics: Apoptosis; Buthionine Sulfoximine; Glioblastoma; Glutathione; Humans; Leukemia; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Sesquiterpenes, Guaiane

Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.

Topics: Acetylation; Active Transport, Cell Nucleus; Amino Acid Sequence; Animals; Antineoplastic Agents; Carcinogenesis; Carrier Proteins; Cell Line, Tumor; Cell Nucleus; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Leukemia; Membrane Proteins; Phosphorylation; Protein Domains; Protein Multimerization; Protein Structure, Quaternary; Sesquiterpenes, Guaiane; Substrate Specificity; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Xenograft Model Antitumor Assays; Zebrafish