title: Eg5 inhibitor, a novel potent targeted therapy, induces cell apoptosis in renal cell carcinoma.
abstract: Eg5 is critical for mitosis and overexpressed in various malignant tumors, which has now been identified as a promising target in cancer therapy. However, the anti-cancer activity of Eg5 inhibitor in renal cell carcinoma (RCC) remains an open issue. In this paper, we evaluated, for the first time, the therapeutic benefit of blocking Eg5 by S-(methoxytrityl)-L-cysteine (S(MeO)TLC) in RCC both in vitro and vivo. The expression of Eg5 was examined in clinical tissue samples and various kidney cell lines, including 293T, 786-0, and OS-RC-2. The anti-proliferative activity of Eg5 inhibitors, (S)-trityl-L-cysteine (STLC) and S(MeO)TLC, was evaluated by a cell viability assay. An apoptosis assay with Hoechst nuclear staining and flow cytometry was applied to investigate the efficacy of the S(MeO)TLC, which is more potent than STLC. Immunofluorescence was used to research the possible mechanism. Furthermore, in vivo studies were performed by using subcutaneous xenograft models, which were used to confirm its role as a potential anti-neoplastic drug. The Eg5 expression was detected in kidney cell lines and RCC tissues, which was low in normal kidney samples. STLC and S(MeO)TLC exhibited their optimal anti-proliferative activity in 72 h, and cells treated with S(MeO)TLC presented characteristic monoastral spindle phenotype in 24 h and apoptotic cells in 48 h. In vivo, S(MeO)TLC effectively suppressed tumor growth in subcutaneous xenograft models. Inhibition of Eg5 represses the proliferation of RCC in vitro and in vivo. All these findings collectively demonstrate that S(MeO)TLC, a potent Eg5 inhibitor, is a promising anti-cancer agent for the treatment of RCC.
authors.affiliation: Department of Urology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, Shandong, China, dingsentai@126.com.
authors.forename: Sentai
authors.initials: S
authors.lastname: Ding
authors.forename: Zuohui
authors.initials: Z
authors.lastname: Zhao
authors.forename: Dingqi
authors.initials: D
authors.lastname: Sun
authors.forename: Fei
authors.initials: F
authors.lastname: Wu
authors.forename: Dongbin
authors.initials: D
authors.lastname: Bi
authors.forename: Jiaju
authors.initials: J
authors.lastname: Lu
authors.forename: Naidong
authors.initials: N
authors.lastname: Xing
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Haihu
authors.initials: H
authors.lastname: Wu
authors.forename: Kejia
authors.initials: K
authors.lastname: Ding
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016547:Kinesins / Q000032:analysis / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D014320:Triphenylmethyl Compounds / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C470243:KIF11 protein, human; C000594388:S-(methoxytrityl)cysteine; D014320:Triphenylmethyl Compounds; C003724:3-tritylthio-L-alanine; D016547:Kinesins; D003545:Cysteine