title: A novel platinum compound inhibits telomerase activity in vitro and reduces telomere length in a human hepatoma cell line.
abstract: Telomerase activity is detectable in most human tumors but not in most normal somatic cells or tissues. Telomerase inhibition has, therefore, been proposed as a novel and potentially selective strategy for antitumor therapy. In the present study, we found that platinum compounds, including cisplatin [cis-diamminedichloro-platinum (II)], strongly inhibited the activity of partially purified rat telomerase. Among the agents tested, 2,3-dibromosuccinato [2-(methylaminomethyl)pyridine]platinum (II) (compound E) exhibited the strongest inhibition, with an median inhibitory concentration (IC(50)) of 0.8 micro M. The mode of inhibition was noncompetitive with either dNTPs or TS (first) primer, with K(i) values estimated to be 2.3 or 3.9 micro M for varied TS primer or dNTPs, respectively. Notably, cisplatin also inhibited the telomerase activity, with an IC(50) of 2.0 micro M. Again, the mode of inhibition was noncompetitive, with K(i) values estimated as 7.3 or 8.1 micro M. Preincubation of TS primer with compound E did not affect the telomerase inhibition, whereas preincubation with cisplatin caused remarkable enhancement. Treatment of a human hepatoma cell line HepG2 with a low concentration of compound E gradually reduced the telomere length, indicating that this compound was able to inhibit telomerase in living cells as well as in vitro.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Furuta
authors.forename: Katsura
authors.initials: K
authors.lastname: Nozawa
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takemura
authors.forename: Shunji
authors.initials: S
authors.lastname: Izuta
authors.forename: Takashi
authors.initials: T
authors.lastname: Murate
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Naoki
authors.initials: N
authors.lastname: Taka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nimura
authors.forename: Shonen
authors.initials: S
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D016922:Cellular Senescence / Q000502:physiology; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D017671:Platinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D017671:Platinum Compounds; D019098:Telomerase; D004259:DNA-Directed DNA Polymerase