title: 2a, a novel curcumin analog, sensitizes cisplatin-resistant A549 cells to cisplatin by inhibiting thioredoxin reductase concomitant oxidative stress damage.
abstract: (1E,4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(5-methylfuran-2-yl)hepta-1,4,6-trien-3-one (2a), a novel curcumin analog, was previously synthesized in our laboratory as a potential thioredoxin reductase (TrxR) inhibitor with excellent growth inhibitory effects on several TrxR over-expressed cancer cells. In this study, our further studies show that 2a is able to inhibit the growth of cisplatin-resistant A549 (A549/CDDP) cells much more effectively in a dose-dependent manner than that of A549 cells in antiproliferative activity experiments. Moreover, 2a-pretreated A549/CDDP cells are sensitive to cisplatin treatment, which is accompanied by the inhibition of TrxR activity in A549/CDDP cells. As a consequence of targeting TrxR, 2a in turn remarkably up-regulates intracellular reactive oxygen species level, depletes glutathione (GSH), and reduces the GSH/GSSG ratio, suggesting that the intracellular redox balance is shifted to a more oxidative state. Consequently, concomitant with the cell growth inhibition of 2a, apoptosis is induced by 2a probably through increased oxidative stress in A549/CDDP cells. In conclusion, these observations demonstrated that TrxR inhibitors would be promising drugs to achieve a successful combinatory or single cancer chemotherapy.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Binhua
authors.initials: B
authors.lastname: Zhou
authors.forename: Jianing
authors.initials: J
authors.lastname: Huang
authors.forename: Yinglin
authors.initials: Y
authors.lastname: Zuo
authors.forename: Baojian
authors.initials: B
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Guo
authors.forename: Baicheng
authors.initials: B
authors.lastname: Cui
authors.forename: Weiyan
authors.initials: W
authors.lastname: Shao
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.forename: Xianzhang
authors.initials: X
authors.lastname: Bu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: C584533:5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(5-methylfuran-2-yl)hepta-1,4,6-trien-3-one; D000970:Antineoplastic Agents; D005663:Furans; D017382:Reactive Oxygen Species; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione; D003474:Curcumin; D002945:Cisplatin; D019803:Glutathione Disulfide