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 / 药物分析学报

ABSTRACT

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-18beta-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 (2 μM) in sensitizing HCC827R(ERL-resistant) cells to ERL.Herein,we first established the selectivity of ERL-induced drug resistance in the HCC827R cells,which was sensitized when ERL was combined with CDODA-Me (2 μ.M),shifting the IC5o from 23.48 μM to 5.46 μM.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 pro-gression transcripts,a reduction of minichromosome maintenance complex components (MCM2-7),all key components of the Cdc45·MCM2-7GINS (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.