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.

Effects of lapatinib on cell proliferation and apoptosis in NB4 cells

“…Previous studies have reported that lapatinib induces autophagic cell death in acute myeloblastic leukemia-derived cell lines ( 17 ); however, we did not detect any changes in the levels of autophagy markers ATG5, ATG7, and LC3II following lapatinib treatment. These contradictory results could be attributed to variations in the concentrations of lapatinib, differences in the time points used in the experiments, cell status, and variations in other experimental factors.…”

“…Moreover, several studies have reported the use of lapatinib in the treatment of leukemia; for example, lapatinib induces apoptosis in cell lines derived from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) ( 15 ), and it has been shown to regulate autophagy, apoptosis, and megakaryocytic differentiation in K562 cells ( 16 ). In addition, lapatinib promotes autophagic cell death and differentiation in AML ( 17 ). Importantly, lapatinib inhibits cell proliferation and promotes cell apoptosis in Philadelphia chromosome-positive acute lymphoblastic leukemia ( 18 ).…”

Circular RNA GRB10 as a competitive endogenous RNA regulating nucleus pulposus cells death in degenerative intervertebral disk

“…A previous study demonstrated that ERBB2 inhibits autophagy via the formation of a complex with Beclin 1, which is a key regulator of autophagy 40 . In addition, lapatinib, a dual tyrosine kinase inhibitor of EGFR and ERBB2, induced autophagic cell death in breast cancer cells overexpressing ERBB2 40 , human hepatoma cells 41 , and acute myeloblastic leukemia 42 . In the present study, circ-GRB10 could regulate ERBB2 expression by sponging miR-328-5p.…”

Blast vacuolization in AML patients indicates adverse-risk AML and is associated with impaired survival after intensive induction chemotherapy

“…We hypothesize that vacuoles in AML blasts may represent dysfunctionally enlarged autophagosomes or other cellular organelles. Indeed, Chen et al (2016) detected a similar blast vacuolization in vitro when treating AML U937 cell lines with lapatinib and demonstrated that these vacuoles appear with lapatinib-induced autophagic cell death [25]. Nevertheless, the blasts require a more detailed ultrastructural analysis and further studies are needed to confirm our findings in a larger cohort and to determine whether this morphological feature can be useful in clinical routine.…”