Intracellular Glutathione Regulates Sesquiterpene Lactone-induced Conversion of Autophagy to Apoptosis in Human Leukemia HL60 Cells

A sesquiterpene lactone, eupalinin A, found in Eupatorium chinense L., exhibited a marked inhibitory effect on cell growth in HL60 cells. In a previous study, it was indicated that the intracellular ROS generation accompanying mitochondrial dysfunction was closely related to the autophagic cell death induced by the treatment with eupalinin A. By glutathione (GSH) pre-treatment, eupalinin A-induced cell growth inhibition was markedly reduced in a time- and dose-dependent manner. Eupalinin A reduced the intracellular GSH level in the early phase, but the GSH pre-treatment reduced this depression. Interestingly, the supplementation of GSH changed the cell death type from autophagic cell death to apoptotic cell death. Pre-treatment with GSH plus p38 MAP kinase inhibitor (SB203580) strongly diminished the eupalinin A-induced autophagic cell death compared with GSH pre-treatment, suggesting a negative regulation of p38 MAP kinase in this cell death type conversion. Taken together, intracellular ROS levels, including GSH, are crucial for the susceptibility to cell death and the determination of type of eupalinin A-induced cell death.