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The ErbB1-dependent effect of recombinant epidermal growth factor (rEGF) against lapatinibinduced cytotoxicity in Caco-2 human intestinal cells
Raja Nur Firzanah Syaza Raja Sharin1, Wan Nor I’zzah Wan Mohamad Zain2, Jesmine Khan3, Mohammad Johari Ibahim4.
Lapatinib, an orally administered dual ErbB1 and ErbB2 tyrosine kinase
inhibitor, is an FDA-approved treatment for ErbB2-positive breast tumour.
However, diarrhoea is one of the major drawbacks for this treatment.
Incidence of lapatinib-induced diarrhoea (LID) has been reported as high as
58-78% of treated patients, with 23.3-25% grade 3-4 cases. Although
diarrhoea seems tolerable, prolonged diarrhoea can cause malnutrition,
hospitalization and interfere with cancer treatment. Thus, diarrhoea can
compromise the quality of life of patients with cancer. ErbB1 is widely
expressed in the intestine which functions to maintain homeostasis. Thus,
ErbB1 is hypothesised to be involved in LID mechanism through its
inhibition by lapatinib in the intestine. The investigation aims to determine
the cytotoxicity effect of lapatinib on Caco-2, a human colon
adenocarcinoma cell line, and to determine whether recombinant epidermal
growth factor (rEGF) could counteract lapatinib action. The experiments
were conducted using water-soluble tetrazolium salt (WST-1) cell viability
assay. Caco-2 was selected as an in vitro model as it is able to differentiate
into enterocytes-like phenotype, hence reflecting small intestinal epithelium.
Caco-2 was treated with a range of concentrations of lapatinib (0-100μM)
and incubated at 24, 48, 72 and 96 hours. Lapatinib showed different
inhibitory concentrations (IC50) at different time-points, with no IC50
observed at 24 hours. Recorded IC50 values are 28μM ±12.81, 29μM ±2.51
and 14μM ±1.64 at 48, 72 and 96 hours, respectively. The median half
maximal IC50 of lapatinib; 28.00μM ±2.51 over 48-96 hours was treated on
Caco-2 in combination with rEGF (150-1000nM). rEGF was able to promote
35.5% cell proliferation in lapatinib-treated cells at 325nM±5.18. Overall,
rEGF counteracts lapatinib-induced cytotoxicity on the intestinal cells which
proves lapatinib interaction with ErbB1 that leads to LID. However further
investigations are required.
Affiliation:
- Universiti Teknologi MARA Cawangan Selangor, Kampus Sungai Buloh, Malaysia
- Universiti Teknologi MARA Cawangan Selangor, Kampus Sungai Buloh, Malaysia
- Universiti Teknologi MARA Cawangan Selangor, Kampus Sungai Buloh, Malaysia
- Universiti Teknologi MARA Cawangan Selangor, Kampus Sungai Buloh, Malaysia
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