Inhibition of telomerase activity in endometrial cancer cells by selenium-cisplatin conjugate despite suppression of its DNA-damaging activity by sodium ascorbate.
Telomerase activation can be considered as a critical step in cell immortalization. The enzyme elongates or maintains telomere length by adding to its end tandem TTAGGG repeats by using its endogenous RNA template. Telomerase is not detectable in most somatic cells but is upregulated in germ line cells and in 85-90% of human cancers, which suggests important role of telomerase in neoplastic transformation. Consequently, telomerase has been proposed as a potentially highly selective target for the development of antiproliferative agents. Platinum complexes are widely administrated in cancer therapy. A conjugate of selenite with diammineplatinum [(NH(3))(2)Pt(SeO(3))(2)] is a novel potential anticancer drug. Using alkaline single cell gel electrophoresis (comet assay), we showed that the drug at 5-30 microM induced concentration-dependent damage to DNA of endometrial cancer cells derived from tumor samples. Sodium ascorbate at 10 and 50 microM reduced the extent of the DNA damage evoked by the drug. (NH(3))(2)Pt(SeO(3)) reduced telomerase activity in the cells in a concentration-dependent manner as measured by using the telomere repeat amplification protocol (TRAP) assay. This effect was independent of sodium ascorbate. Therefore, mutagenic effects of the conjugate can be reduced by well-recognized antimutagen, sodium ascorbate, but it can still retain ability to affect neoplastic transformation. The results obtained indicate that (NH(3))(2)Pt(SeO(3)) may specifically inhibit telomerase activity in endometrial cancer cells.
Błasiak
Janusz
J
Department of Molecular Genetics, University of Lodz, Lodz, Poland. januszb@biol.uni.lodz.pl
Kadłubek
Magdalena
M
Kowalik
Joanna
J
Romanowicz-Makowska
Hanna
H
Pertyński
Tomasz
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000201:enzymology*; D005260:Female; D006801:Humans; D016133:Polymerase Chain Reaction; D018036:Selenium Compounds / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere
D000970:Antineoplastic Agents; D000975:Antioxidants; D018036:Selenium Compounds; C110743:selenium-cisplatin conjugate; D019098:Telomerase; D001205:Ascorbic Acid; D002945:Cisplatin