title: Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells.
abstract: Although the molecular therapeutics targeting key biomarkers such as epithelial growth factor receptor (EGFR), PI3K/AKT/mTOR, and vascular endothelial growth factor (VEGF) shows some success in clinical trials, some internally existing challenges in endothelial cancer biology hinder the drug effects. One of the major challenges stems from cancer stem cell-derived drug resistance. CD133 positive cells are well believed as cancer stem cells (CSC) in endometrial cancers and NOTCH pathway plays a critical role in retaining CD133+ cells by promoting CSC self-renewal and chemoresistance. Here, we initiated a therapeutic strategy to improve effects of EGFR inhibition by targeting NOTCH pathway of CD133+ cells in endometrial cancers. We first detected and purified the CD133+ cell fraction in endometrial cancer cell line Ishikawa (IK), and validated activation of NOTCH pathway in the CD133+ cells that have higher proliferation rate and lower apoptosis rate, comparing to CD133- cells. Results of nude mouse xenograft experiments further demonstrated CD133+ cells retain higher tumorigenesis capacity than CD133- cells, indicating their tumor-initiating property. Last, we applied both NOTCH inhibitor DAPT and EGFR inhibitor AG1478 treatment on endometrial cancer lines IK and HEC-1A and the results suggested improvement effects of the combination therapy compared to the treatments of DAPT or AG1478 alone. These findings indicated targeting NOTCH pathway in CD133+ cells, combining with EGFR inhibition, which provides a novel therapeutic strategy for endometrial cancer diseases.
authors: a Department of Neurobiology , China Medical University , Shenyang , P. R. China.
authors: Chao
authors: C
authors: Shang
authors: b School of Health Sciences , Macao Polytechnic Institute , Macao , P. R. China.
authors: Bin
authors: B
authors: Lang
authors: b School of Health Sciences , Macao Polytechnic Institute , Macao , P. R. China.
authors: Li-Rong
authors: LR
authors: Meng
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D003959:Diamines / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C000612000:24-diamino-5-phenylthiazole; D000071916:AC133 Antigen; D003959:Diamines; C000606023:PROM1 protein, human; D011799:Quinazolines; D051880:Receptors, Notch; D013844:Thiazoles; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Cancer stem cell; EGFR; NOTCH; endometrial cancer