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Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

Yu-Jen Chen1, Li-Wen Fang2, Wen-Chi Su3

  • 1Department 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.

Oncotargets and Therapy
|August 9, 2016
PubMed

Insights

Lapatinib, an EGFR inhibitor, shows anticancer effects against leukemia cells by inducing apoptosis and autophagic cell death. It also promotes macrophagic differentiation and synergizes with cytotoxic drugs, suggesting potential as a novel leukemia treatment.

Area of Science:

  • Pharmacology
  • Oncology
  • Cell Biology

Background:

  • Lapatinib is an oral dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) superfamily.
  • Its anticancer activity has been established, prompting investigation into its effects on various leukemia cell lines.

Purpose of the Study:

  • To investigate the effects and underlying mechanisms of lapatinib on human acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells.
  • To explore lapatinib's potential as a novel antileukemia agent.

Main Methods:

  • Treatment of leukemia cell lines (U937, HL-60, NB4, KU812, MEG-01, Jurkat) with lapatinib.
  • Assessment of cell growth inhibition, apoptosis, and non-apoptotic cell death.
  • Analysis of autophagy markers (acridine orange staining, electron microscopy, LC3-II, ATG5, ATG7), autophagy inhibition (3-methyladenine, shRNA), macrophagic differentiation markers (CD14, CD68, ROS), and synergistic effects with cytotoxic drugs.

Main Results:

  • Lapatinib inhibited the growth of all tested leukemia cell lines.
  • It induced apoptosis in HL-60, NB4, and Jurkat cells, and non-apoptotic cell death in U937, K562, and MEG-01 cells.
  • Lapatinib triggered autophagic cell death and macrophagic differentiation in AML U937 cells, and demonstrated synergistic effects with cytotoxic drugs.

Conclusions:

  • Lapatinib exhibits significant antileukemia activity through diverse cell death pathways, including apoptosis and autophagy.
  • The induction of macrophagic differentiation and synergistic effects with conventional drugs highlight lapatinib's therapeutic potential.
  • Lapatinib warrants further development as a novel agent for treating leukemia.
Keywords:
AMLautophagic cell deathdifferentiationlapatinibleukemia

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