title: Chronopharmacology and mechanism of antitumor effect of erlotinib in Lewis tumor-bearing mice.
abstract: The epidermal growth factor receptor (EGFR), a ubiquitously expressed receptor tyrosine kinase, is recognized as a key mediator of tumorigenesis in many human epithelial tumors. Erlotinib is tyrosine kinase inhibitor approved by FDA for use in oncology. It inhibits the intracellular phosphorylation of tyrosine kinase associated with the EGFR to restrain the development of the tumor. To investigate the antitumor effect of erlotinib at different dosing times and the underlying molecular mechanism via the PI3K/AKT pathway, we established a mouse model of Lewis lung cancer xenografts. The tumor-bearing mice were housed four or five per cage under standardized light-dark cycle conditions (light on at 7:00 AM, 500 Lux, off at 7:00 PM, 0 Lux) with food and water provided ad libitum. The mice were observed for quality of life, their body weight and tumor volume measured, and the tumor growth curves drawn. After being bled, the mice were sacrificed by cervical dislocation. The tumor masses were removed at different time points and weighed. The mRNA expression of EGFR, AKT, Cyclin D1 and CDK-4 were assayed by quantitative real-time PCR (qRT-PCR). Protein expression levels of AKT, P-AKT and Cyclin D1 were determined by Western blot analysis. The results suggest that erlotinib has a significant antitumor effect on xenografts of non-small cell lung cancer in mice, and its efficacy and toxicity is dependent on the time of day of administration. Its molecular mechanism of action might be related to the EGFR-AKT-Cyclin D1-CDK-4 pathway which plays a crucial role in the development of pathology. Therefore, our findings suggest that the time of day of administration of Erlotinib may be a clinically important variable.
authors.affiliation: Department of Pharmacology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Hand Surgery Center of the Whole Army, No. 401 Hospital of Chinese People's Liberation Army, Qingdao, China.
authors.forename: Fengmei
authors.initials: F
authors.lastname: An
authors.affiliation: Department of Oncology, No. 401 Hospital of Chinese People's Liberation Army, Qingdao, China.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: Department of Pharmacology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, No. 401 Hospital of Chinese People's Liberation Army, Qingdao, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Pharmacy, No. 401 Hospital of Chinese People's Liberation Army, Qingdao, China.
authors.forename: Mingchun
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010750:Phosphoproteins; D011799:Quinazolines; D019938:Cyclin D1; D000069347:Erlotinib Hydrochloride; D051057:Proto-Oncogene Proteins c-akt