Abstract
Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.
Highlights
Epidermal growth factor receptors (EGFR or ErbB/Her) belong to the receptor tyrosine kinase superfamily
We evaluated the effect of lapatinib on cell death and differentiation, and investigated its mechanism of action in human chronic myelogenous leukemia (CML) K562 cells
We found that lapatinib induced multiple cellular events simultaneously including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells
Summary
Epidermal growth factor receptors (EGFR or ErbB/Her) belong to the receptor tyrosine kinase superfamily. Due to the pivotal roles of aberrant EGFR signaling pathways in the development of different kinds of malignant human cancers, the receptor tyrosine kinase superfamily is well-studied. Among the ErbB receptors, ErbB2 lacks its own ligands; ErbB2 forms heterodimers with EGFR, ErbB3 or ErbB4, or even with other family members, such as Insulin-like growth factor-1 receptor (IGF-1R) [5,6]. Findings such as these suggest that the ErbBs may be good molecular targets for various malignancies, including breast cancer
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