Abstract
Lapatinib is an orally administered, dual ErbB1/ErbB2 tyrosine kinase inhibitor (TKI). It is effective in ErbB2 + ve breast cancer treatment. However, lapatinib is associated with diarrhoea with an incidence of 47–75%. The mechanism of ErbB1 TKI-induced diarrhoea remains unclear. ErbB1 or epidermal growth factor receptor (EGFR) is expressed in gastrointestinal mucosa whereby the primary site for drug absorption is intestine. Thus, administration of ErbB1 oral TKI may disrupt gut homeostasis, leading to diarrhoea. Nevertheless, further investigations are required. We observed that lapatinib inhibited 50% Walker 256 breast tumour cells and IEC-6 small intestinal cell growth. Higher percentage of necrosis was observed in lapatinib-treated Walker 256. Lapatinib-treated IEC-6 showed higher percentage of late apoptosis. Only ErbB2 mRNA was detected in Walker 256 but both ErbB1 and ErbB2 mRNAs were detected in IEC-6, yet both protein staining were detected in both cells. Lapatinib exhibited cytotoxic properties on ErbB1/ErbB2 expressing cell lines, with intestinal cells being more sensitive to lapatinib compared to tumour cells. Lapatinib induced necrosis in tumour cells, while inducing late apoptosis in intestinal cells may explain lapatinib-induced diarrhoea in patients administered with the drug which could be due to apoptosis of intestinal epithelial cells leading to barrier disruption and consequently diarrhoea.
Highlights
ErbB1 and ErbB2 play significant roles in ligand-activated signalling pathways that regulate cell proliferation and cell death [1]
Fluorescein isothiocyanate (FITC) Annexin V Apoptosis Detection Kit I, which consists of 10× Annexin V binding buffer, FITC Annexin V and propidium iodide (PI) staining solutions was obtained from BD Pharmingen, San Diego, CA, USA
Walker 256 and IEC-6 were treated with lapatinib at a series of concentrations (1–10 μM) to Biomedicines 2020, 8, x FOR PEER REVIEW
Summary
ErbB1 and ErbB2 play significant roles in ligand-activated signalling pathways that regulate cell proliferation and cell death [1]. There were breast cancer cell lines which showed high lapatinib cytotoxic effect (MDA-MB-175: 0.012 μM, EFM-19: 4.6 μM, MCF-7: 7.7 μM and MDA-MB-435: 8.5 μM) but expressed a moderate or low level of both ErbB1 and ErbB2 (2.2 to 20 ng/mg) [12,13]. There were breast cancer cell lines with high lapatinib cytotoxic effect (MDA-MB-468: 4.7 μM and BT20: 9.8 μM) that correlated with higher ErbB1 expression (295 to 908 ng/mg). Understanding the effect of lapatinib on Walker 256 rat breast tumour and IEC-6 rat normal intestinal cells would increase the potential of the cell lines to be used in developing an appropriate rat tumour model to study tyrosine kinase inhibitor-induced gastrointestinal toxicity, in particular lapatinib-induced gastrointestinal toxicity to reflect breast cancer patient setting receiving lapatinib treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
