RRC ID 52298
Author Kunimasa K, Nagano T, Shimono Y, Dokuni R, Kiriu T, Tokunaga S, Tamura D, Yamamoto M, Tachihara M, Kobayashi K, Satouchi M, Nishimura Y.
Title Glucose metabolism-targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor-induced drug-tolerant persisters.
Journal Cancer Sci
Abstract In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor-tyrosine kinase inhibitor-induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR-mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell-related markers by quantitative RT-PCR and the expression of the cellular senescence-associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem-like cell targeting drug, withaferin A. Drug-tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem-like cells (CSCs) and the other with the properties of therapy-induced senescent (TIS) cells. The CD133high cell population had CSC properties and the CD133low cell population had TIS properties. The CD133low cell population containing TIS cells showed a senescence-associated secretory phenotype that supported the emergence of the CD133high cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133low cell population. Withaferin A effectively eliminated the CD133high cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib-resistant tumor growth.
Volume 108(7)
Pages 1368-1377
Published 2017-7
DOI 10.1111/cas.13266
PMID 28445002
PMC PMC5497794
MeSH Adenocarcinoma Adenocarcinoma of Lung Animals Blotting, Western Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Cellular Senescence / drug effects Drug Resistance, Neoplasm / physiology* ErbB Receptors / antagonists & inhibitors Flow Cytometry Gefitinib Glucose / metabolism Humans Lung Neoplasms Mice Mice, Inbred BALB C Mice, Nude Molecular Targeted Therapy / methods Neoplastic Stem Cells / drug effects* Neoplastic Stem Cells / pathology Phloretin / pharmacology* Polymerase Chain Reaction Protein Kinase Inhibitors / pharmacology Quinazolines / pharmacology Withanolides / pharmacology* Xenograft Model Antitumor Assays
IF 4.751
Times Cited 5
Human and Animal Cells II-18(RCB2093)