Lapatinib-induced ErbB1 Inhibition Modulates Caco-2 Intestinal Permeability Through Tight Junction Alteration

Abstract

Abstract Lapatinib (LAP), a dual ErbB1 and ErbB2 tyrosine kinase inhibitor, is effective in ErbB2-positive breast cancer treatment but is associated with diarrhoea. ErbB1 is expressed in the intestine; thus, it is hypothesised that lapatinib inhibits normal ErbB1 function, causing diarrhoea. This study investigated the possible involvement of ErbB1 inhibition in the underlying mechanism of lapatinib-induced diarrhoea. Caco-2 intestinal monolayers were treated with LAP and LAP in combination with recombinant epidermal growth factor (LAP+rEGF). Transepithelial electrical resistance (TEER) of the Caco-2 monolayer and paracellular transport of Lucifer yellow were measured, while the expression of the tight junction proteins (TJPs) claudin-1, occludin, and ZO-1 and the inflammatory cytokines TNF-α, IL-1β, and IL-6 were determined using qPCR and immunofluorescence staining. LAP significantly decreased TEER compared to the control untreated monolayer (p < 0.05) at 96 hours. Higher Lucifer yellow permeability was observed in the LAP group but was not significantly different from that in the control group. LAP suppressed the mRNA and protein expression of TJPs, whereas cotreatment with rEGF counteracted LAP inhibition (p < 0.05). No significant changes were observed in the mRNA expression levels of inflammatory cytokines in the LAP group. Surprisingly, rEGF treatment increased IL-6 mRNA expression (p < 0.01). However, it is suggested that IL-6 is involved in intestinal epithelial proliferation induced by rEGF rather than inflammation. Lapatinib increased Caco-2 intestinal monolayer permeability and reduced tight junction expression by inhibiting ErbB1 expression, suggesting a mechanism of lapatinib-induced diarrhoea.