title: Inhibition of glutathione synthesis eliminates the adaptive response of ascitic hepatoma 22 cells to nedaplatin that targets thioredoxin reductase.
abstract: Thioredoxin reductase (TrxR) is a target for cancer therapy and the anticancer mechanism of cisplatin involves TrxR inhibition. We hypothesize that the anticancer drug nedaplatin (NDP), an analogue of cisplatin and a second-generation platinum complex, also targets TrxR. Furthermore, we investigate whether the therapeutic efficacy of NDP can be enhanced by simultaneous modulation of 1) TrxR, via NDP, and 2) glutathione (GSH), via the GSH synthesis inhibitor buthionine sulfoximine (BSO). Mice bearing ascitic hepatoma 22 (H22) cells were treated with NDP alone or NDP plus BSO. TrxR activity of H22 cells was inhibited by NDP in a dose-dependent manner. A high correlation between the inhibition of TrxR activity at 6h and the inhibition of ascitic fluid volume at 72h was established (r=0.978, p<0.01). As an adaptive response, the viable ascitic cancer cells after NDP treatment displayed an enlarged cell phenotype, assembled with several-fold more antioxidant enzymes and GSH-predominant non-protein free thiols. This adaptive response was largely eliminated when BSO was co-administered with NDP, leading to the decimation of the H22 cell population without enhancing renal toxicity, since at this dose, NDP did not inhibit renal TrxR activity. In conclusion, the pharmacological effect of NDP involves TrxR inhibition, and the adaptive response of NDP-treated ascitic H22 cells can be efficiently counteracted by BSO. Simultaneous modulation of TrxR and GSH on ascitic H22 cells using NDP plus BSO greatly enhances therapeutic efficacy as compared with the single modulation of TrxR using NDP alone.
authors.affiliation: School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui, PR China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Lu
authors.forename: Dongxu
authors.initials: D
authors.lastname: Wang
authors.forename: Shengrong
authors.initials: S
authors.lastname: Li
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wan
authors.forename: Ethan Will
authors.initials: EW
authors.lastname: Taylor
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001201:Ascites / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009944:Organoplatinum Compounds; D019328:Buthionine Sulfoximine; C053989:nedaplatin; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione