title: Characterization of the cytotoxic activity of [2]rotaxane (TRO-A0001), a novel supramolecular compound, in cancer cells.
abstract: Rotaxanes comprise a class of interlocked molecules containing a wheel threaded onto an axle with blocking groups on the ends to keep the wheel from sliding off. Here, we show that [2][bis(2-(3,5-dimethylphenylcarbonyloxy)ethyl) ammoniumtrifluoromethanesulfonate]-[dibenzo-24-crown-8] rotaxane (TRO-A0001), a rotaxane compound, exerted a growth inhibitory effect on several human cancer cell lines. An MTT assay revealed an IC50 of 14-830 nM for TRO-A0001 in these cells. Neither the wheel nor the axle part alone inhibited tumor cell growth, suggesting that the complete rotaxane molecule with its unique "intramolecular mobility" is required to inhibit cell growth. Annexin-V/PI staining provided evidence of the induction of apoptosis, which was further confirmed by the observation of poly (ADP-ribose) polymerase cleavage. Furthermore, a cell cycle analysis using flow cytometry showed that TRO-A0001 treatment resulted in G1 arrest in glioblastoma T98G and melanoma G361 cells. An immunoblot analysis revealed that in both cell lines, TRO-A0001 treatment caused the induction of p21/Cip1, thereby down-regulating Cdks 2, 4 and 6 and reducing Cyclins D1 and E. The results presented in this study demonstrate cytotoxicity of the rotaxane compound and its potential as a lead compound for the development of a chemotherapeutic agent against cancer.
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Medicinal-Informatics and Research Unit, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Organic and Polymeric Materials, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo, 152-8552, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Organic and Polymeric Materials, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo, 152-8552, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Takata
authors.affiliation: Miki Health Science Research Institute, 2-14-7 Hiigawa, Jonan-ku, Fukuoka, 814-0153, Japan.
authors.forename: Nobufumi
authors.initials: N
authors.lastname: Ono
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. knishio@med.kindai.ac.jp.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D008970:Molecular Weight; D043862:Rotaxanes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D043862:Rotaxanes; C000613908:TRO-A0001
keywords: Apoptosis; Cancer; G1 cell-cycle arrest; Rotaxane; Supramolecular compound; p21/Cip1