Chronopharmacodynamics and mechanisms of antitumor effect induced by erlotinib in xenograft-bearing nude mice

Abstract

Receptor tyrosine kinases, mediators of a variety of critical cellular functions, contribute to tumor progression and metastasis. The epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase family, is ubiquitously expressed on the surface of mammalian cells. Erlotinib hydrochloride (Tarceva) can inhibit the intracellular phosphorylation of tyrosine kinases. To investigate the influence of dosing time on the ability of erlotinib to inhibit tumor growth and the underlying molecular mechanisms via the PI3K/AKT and ERK/MAPK pathway, we established nude mice HCC827 tumor xenografts models. The tumor-bearing mice were housed 3–4 per cage under standardized light/dark cycle conditions (lights on at 07:00 h, off at 19:00 h) with food and water ad libitum. The mice were randomly divided into erlotinib treated groups and control groups, gavaged with erlotinib and vehicle respectively at 6 different time points for 21 days. To draw tumor growth curves, the tumor volume was measured every three days. After the mice were sacrificed, the tumor masses of each group were removed and weighed. The relative protein expression levels of p-EGFR, p-AKT and p-MAPK were assayed at 4 h after erlotinib or vehicle gavage by Western blot analysis. The antitumor effect of erlotinib presented diurnal rhythmicity. The growth of HCC827 xenograft was more potently inhibited by erlotinib in the early light phase than in the early dark phase (p < 0.05). The inhibitory effect of erlotinib on phosphorylation of EGFR, AKT and MAPK varied with its administration time. The results indicate that the antitumor effect of erlotinib is more potent when the drug was administered when the activities of EGFR and its downstream factors increased. Our findings may provide a clue to optimize the dosing schedule of erlotinib.