title: Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia.
abstract: Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her) superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA) partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of macrophagic differentiation in AML U937 cells by lapatinib. We also noted the synergistic effects of the use of lapatinib and cytotoxic drugs in U937 leukemia cells. These results indicate that lapatinib may have potential for development as a novel antileukemia agent.
authors: Department of Medical Research; Department of Radiation Oncology, Mackay Memorial Hospital; Institute of Traditional Medicine, School of Medicine, National Yang-Ming University; Institute of Pharmacology, Taipei Medical University, Taipei.
authors: Yu-Jen
authors: YJ
authors: Chen
authors: Department of Nutrition, I-Shou University, Kaohsiung.
authors: Li-Wen
authors: LW
authors: Fang
authors: Research Center for Emerging Viruses, China Medical University Hospital; Graduate Institute of Clinical Medical Science, China Medical University, Taichung.
authors: Wen-Chi
authors: WC
authors: Su
authors: Department of Medical Research.
authors: Wen-Yi
authors: WY
authors: Hsu
authors: Department of Medical Research.
authors: Kai-Chien
authors: KC
authors: Yang
authors: Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Republic of China.
authors: Huey-Lan
authors: HL
authors: Huang
keywords: AML; autophagic cell death; differentiation; lapatinib; leukemia