title: Thioredoxin reductase inhibitor ethaselen increases the drug sensitivity of the colon cancer cell line LoVo towards cisplatin via regulation of G1 phase and reversal of G2/M phase arrest.
abstract: We evaluated the combination treatment of ethaselen (BBSKE) as a thioredoxin reductase (TrxR) inhibitor plus cisplatin (CDDP) on the human colon adenocarcinoma cell line LoVo. Therapeutic effects ranging from nearly additive to clearly synergistic demonstrated an effective combination, i.e., the cytostatic dose of CDDP could be reduced without a loss in efficacy. To further investigate the cellular response mechanisms of these favorable outcomes, we analyzed the cell-cycle profiles, mRNA expression patterns, and protein levels of several key genes after incubation with BBSKE or CDDP separately and in combination. In appropriate conditions, CDDP induced arrest at the G2/M phase accompanied by the enhanced inhibitory phosphorylation of Cdk1 and the elevated protein expression of cyclin B1. BBSKE downregulated expression of cyclin D1 by increasing mRNA and protein levels of p21, and thus induced G1 phase arrest. BBSKE returned Cdk1 to an activated state, and reduced the protein level of cyclin B1 after incubation in combination with CDDP, which was consistent with the reduction in the percentage of cells in G2/M identified by flow cytometry. By regulating the G1 phase and reversing CDDP-induced G2/M phase arrest, BBSKE increases drug sensitivity of LoVo cells toward CDDP, and probably provides a meaningful anticancer strategy for further clinical studies.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Fu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tan
authors.forename: Han-Wei
authors.initials: HW
authors.lastname: Yin
authors.forename: Kun
authors.initials: K
authors.lastname: Xiong
authors.forename: Tian-Yu
authors.initials: TY
authors.lastname: Wang
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Ren
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Zeng
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C478160:(1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone))ethane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009363:Neoplasm Proteins; D016566:Organoselenium Compounds; D013880:Thioredoxin-Disulfide Reductase; D002945:Cisplatin