ZH-1 enhances the anticancer activity of gemcitabine via deoxyribonucleotide synthesis and apoptotic pathway against A549 cells. (September 2018)

• Record Type: Journal Article
• Authors: Guo, Jianru; Li, Yan; Lam, Christopher Wai Kei; Wang, Caiyun; Yao, Meicun; Zhang, Wei
• Is Part Of: Food and chemical toxicology. Volume 119(2018)
• Page Start: 222
• Page End: 230
• Publication Date: 2018-09
• Subjects: Gemcitabine -- ZH-1 -- Apoptosis -- Deoxyribonucleotides -- Intrinsic apoptotic pathway; ATCC American Type Culture Collection -- ATP adenosine-triphosphate -- ATP13C15N trioctylamine, 1, 1, 2-trichlorotrifluoroethane, stable isotope labeled adenosine-13C1015N5-triphosphate -- CI combination index -- CMP cytidine monophosphate -- CTP cytidine triphosphate -- Ctr control group -- dAMP deoxyadenosine monophosphate -- dATP deoxyadenosine triphosphate -- dCDP deoxycytidine diphosphate -- dCTP deoxycytidine triphosphate -- dFdC gemcitabine -- DEA diethylamine -- dFdCDP gemcitabine diphosphate -- dFdCMP gemcitabine monophosphate -- dFdCTP gemcitabine triphosphate -- dGTP deoxyguanosine triphosphate -- dNTPs deoxyribonucleotide triphosphates -- dRNs deoxyribonucleotides -- dTMP deoxythymine monophosphate -- dTTP deoxythymidine triphosphate -- FBS fetal bovine serum -- GTP guanosine triphosphate -- HA Hexylamine -- MRM multiple reactions monitoring -- MTT 3-[(4, 5)-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide -- NSCLC non-small-cell lung cancer -- PARP poly-ADP-ribose polymerase -- PBS phosphate buffer saline -- PLS-DA partial least squares discriminant analysis -- RNs ribonucleotides -- RR ribonucleotide reductase -- TCA trichloroacetic acid -- UTP uridine triphosphate -- 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); Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2018.04.019
• Languages: English
• ISSNs: 0278-6915

Abstract

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 A549 cells. MTT assay showed that the combined use of gemcitabine and ZH-1 presented a significant inhibition effect on A549 cell growth with the cell viability from 82.3 ± 5.6% to 51.0 ± 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 A549 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. Highlights: The inhibitory effect of ZH-1 and its potential interactions with gemcitabine in A549 cells was investigated. The combined treatment of gemcitabine and ZH-1 on the levels of ribonucleotides and deoxyribonucleotides was demonstrated. The combined use of gemcitabine and ZH-1 in A549 cells enhanced induction of apoptosis via the intrinsic pathway.