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    국제 암학술대회 발표 (Poster, 2004.10)
    CONFERENCE  komipharm 2014.03.18 15:54

16thEORTC-NCI-AACR Geneva,Switzerland


436The novel compound KML001 induces telomere attrition,senescence and chromosomal instability in cell
lines with  short 
telomeres


 Hendriks, H.R.; Dai, F.;Rademaker, B.; Yang,Y.J.; Lee, S.B.; Burger, A.M.

 

Arsenic trioxideis experiencing a revival in cancer medicine since it has proven effective inthe treatment of acute promyelocytic leukemia. Its mechanisms of action arecurrently being revisited to  enable rational use of inorganic arsenic.Induction of apoptosis and reactive oxygen species, as well  as striking effectson telomeres and telomerase have been described. The novel arsenic  compoundKML001 has shown preclinical activity in solid tumors and has just enteredclinical trials.  This study was initiated in order to investigate whetherKML001 can target telomeres and telomerase.  MCF-7 (6 kb), a human breast cancercell line with longer telomeres, PC3 (3, 5 kb) and UXF 1138L  (2.5 kb), prostateand uterus cancer cell lines respectively with shorter telomeres, were chosenfor in  vitroexperiments. The TRAP assay (telomeric repeatamplification protocol) was used to measure  telomerase activity, β-galactosidase staining fordetection of cellular senescence, the  sulforhodamine B assay forproliferation tests, Southern blotting to determine mean telomere  fragmentlength (TRF), and fluorescence in situ hybridization (FISH) with human centromere and  telomereprobes to study chromosomal integrity. The IC50for KML001 in PC3 cells was 1 μM, in MCF-7=4 μM, and in UXF 1138L=5 μM. KML001treatment at doses around the IC50 potentlyshortened telomeres in PC3 and UXF 1138L, but not MCF-7 cells under continuousexposure.