Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells  

作　　者：Ebony Nottingham Elizabeth Mazzio Sunil Kumar Surapaneni Shallu Kutlehria Arindam Mondal Ramesh Badisa Stephen Safe Arun K.Rishi Mandip Singh 

机构地区：[1]Department of Pharmaceutics,College of Pharmacy and Pharmaceutical Sciences,Florida A&M University,Tallahassee,FL,32307,USA [2]Department of Veterinary Physiology and Pharmacology,College of Veterinary Medicine,Texas A&M University,College Station,TX,77843,USA [3]John D.Dingell VA medical Center and Department of Oncology,Wayne State University,Detroit,MI,48201,USA

出　　处：《Journal of Pharmaceutical Analysis》2021年第6期799-807,共9页药物分析学报（英文版）

基　　金：National Institute on Minority Health and Health Disparities(National Institutes of Health,Grant/Award No.:U54 MD007582);NSF-CREST Center for Complex Materials Design for Multidimensional Additive Processing(Co Man D,Grant/Award No.:1735968)for providing the funding for this research。

摘　　要：Non-small cell lung cancer(NSCLC)is often characterized by an underlying mutation in the epidermal growth factor receptor(EGFR),contributing to aggressive metastatic disease.Methyl 2-cyano-3,11-dioxo-18 beta-olean-1,12-dien-30-oate(CDODA-Me),a glycyrrhetinic acid derivative,reportedly improves the therapeutic response to erlotinib(ERL),an EGFR tyrosine kinase inhibitor.In the present study,we performed a series of studies to demonstrate the efficacy of CDODA-Me(2μM)in sensitizing HCC827 R(ERL-resistant)cells to ERL.Herein,we first established the selectivity of ERL-induced drug resistance in the HCC827 R cells,which was sensitized when ERL was combined with CDODA-Me(2μM),shifting the IC50 from 23.48μM to 5.46μM.Subsequently,whole transcriptomic microarray expression data demonstrated that the combination of ERL+CDODA-Me elicited 210 downregulated genes(0.44%of the whole transcriptome(WT))and 174 upregulated genes(0.36%of the WT),of which approximately 80%were unique to the ERL+CDODA-Me group.Synergistic effects centered on losses to cell cycle progression transcripts,a reduction of minichromosome maintenance complex components(MCM2-7),all key components of the Cdc45·MCM2-7 GINS(CMG)complex,and replicative helicases;these effects were tantamount to the upregulation of processes associated with the nuclear factor erythroid 2 like 2 translational response to oxidative stress,including sulfiredoxin 1,heme oxygenase 1,and stress-induced growth inhibitor 1.Collectively,these findings indicate that the synergistic therapeutic effects of ERL+CDODA-Me on resistant NSCLC cells are mediated via the inhibition of mitosis and induction of oxidative stress.

关 键 词：Transcriptomic analysis Combination therapy Drug resistance ERLOTINIB Epidermal growth factor receptor 

分 类 号：R734.2[医药卫生—肿瘤]