Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8546769 | Food and Chemical Toxicology | 2018 | 37 Pages |
Abstract
The purpose of this study was to investigate the inhibitory effect of ZH-1 ((6S,9aS,6aR,9bR)-6-(phenylcarbonyl)-6,6a,9a,9b-tetrahydro-8H-azolidino[3,4-a]b enzo [e]indolizine-7,9-dione) and its potential interaction with gemcitabine in A549â¯cells. MTT assay showed that the combined use of gemcitabine and ZH-1 presented a significant inhibition effect on A549â¯cell growth with the cell viability from 82.3â¯Â±â¯5.6% to 51.0â¯Â±â¯6.6%. The CI value was 0.60 suggesting a synergistic effect between these two drugs. HPLC-MS/MS data indicated that combined treatment with gemcitabine and ZH-1 induced a significant decrease in deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate and deoxythymidine triphosphate levels compared with use of gemcitabine alone. Five RNs as well as seven dRNs were considered to be significantly contributive to the discrimination of samples. Furthermore, western blot analysis revealed that the combination treatment caused A549â¯cell apoptosis via the intrinsic pathway by up-regulating Bax/Bcl-2 ratio, activating caspase-9, caspase-3 and poly-ADP-ribose polymerase, and promoting caspase-7, caspase-9 and poly-ADP-ribose polymerase cleavage. Collectively, the combined treatment with gemcitabine and ZH-1 exerted a strong synergistic action on anticancer activity through growth inhibition, perturbations in ribonucleotides and deoxyribonucleotides and the activation of intrinsic apoptotic signaling pathway.
Keywords
MRMdATPdCTPDTTPdGTPdeoxyribonucleotidesCTPUTPPARPATCCDCDPCMPdFdCCTRRNSPLS-DAdeoxyadenosine monophosphatePBSdFdCMPFBSdFdCTPGTPDEATCADTMPDAMPIntrinsic apoptotic pathwaydNTPSMTTAdenosine-triphosphateATPtrichloroacetic acidUridine triphosphatePartial least squares discriminant analysisdeoxyribonucleotide triphosphatesGemcitabineApoptosisdeoxycytidine triphosphatedeoxyadenosine triphosphatedeoxyguanosine triphosphatedeoxythymidine triphosphatediethylamineribonucleotidesRibonucleotide reductaseNon-small-cell lung cancerNSCLCfetal bovine serumCytidine triphosphateCytidine monophosphatecombination indexphosphate buffer salineAmerican Type Culture Collectionmultiple reactions monitoringHexylaminepoly-ADP-ribose polymerasecontrol groupGuanosine triphosphate
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Authors
Jianru Guo, Yan Li, Christopher Wai Kei Lam, Caiyun Wang, Meicun Yao, Wei Zhang,