A novel platinum compound inhibits telomerase activity in vitro and reduces telomere length in a human hepatoma cell line.

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 (IC₅₀) of 0.8 μM. 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 μM for varied TS primer or dNTPs, respectively. Notably, cisplatin also inhibited the telomerase activity, with an IC₅₀ of 2.0 μM. Again, the mode of inhibition was noncompetitive, with K_i values estimated as 7.3 or 8.1 μM. 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. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]