Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme

被引:24
作者
Colangelo, D
Ghiglia, AL
Viano, I
Cavigiolio, G
Osella, D
机构
[1] Univ Piemonte Orientale A Avogadro, Dipartimento Sci & Tecnol Avanzate, I-15100 Alessandria, Italy
[2] Univ Piemonte Orientale A Avogadro, Dipartimento Sci Med, I-28100 Novara, Italy
关键词
anticancer chemotherapy; apoptosis; metallo-pharmaceuticals; platinum complexes; telomerase inhibitors;
D O I
10.1023/A:1023428315746
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Since it has been widely demonstrated that platinum-based drugs, like cisplatin, carboplatin and oxaliplatin, bind preferentially to guanine in N7 position and that telomerase assemblage includes a RNA portion rich in guanine, we previously designed and synthesized a series of new complexes with a cytotoxic [Pt(II)Cl-2] moiety, with the aim of selecting carrier ligands able to inhibit telomerase enzyme. Among these compounds, [cis-dichloropyridine-5- 5-isoquinolinesulfonic acid Pt(II)], named Ptquin8, showed the most significant inhibition of telomerase in a cell-free biochemical assay. In this paper, we report the biological effects of Ptquin8 on in vitro tumor model (MCF-7). This complex is able to reduce telomerase activity from 12 to 46%, in a concentration range between 10(-9) and 10(-5) M after 24 h continuous treatment. Moreover, Ptquin8 shows significant cytotoxicity after 10 days of continuous treatment only at concentrations higher than 10(-5) M. The determination of residual telomere length confirmed the inhibition of telomerase action. This induced a progressive reduction of the cell proliferative capacity, and the appearance of an elevated number of apoptotic cells after 18 days. RT-PCR analysis of telomerase RNA components excluded any interaction of the compound at genomic level. The biochemical effects of Ptquin8 were also evaluated on non-neoplastic NIH3T3 cells, that are able to down-regulate telomerase activity as a consequence of the confluence contact inhibition. In this cell model, the reactivation of telomerase due to re-seeding at lower density was significantly inhibited by Ptquin8 in a dose-dependent manner. These results highlight a possible role of Ptquin8 as a selective anti-telomerase tool for cancer treatment.
引用
收藏
页码:553 / 560
页数:8
相关论文
共 27 条
[1]   Cytostatic concentrations of anticancer agents do not affect telomerase activity of leukaemic cells in vitro [J].
Akiyama, M ;
Horiguchi-Yamada, J ;
Saito, S ;
Hoshi, Y ;
Yamada, O ;
Mizoguchi, H ;
Yamada, H .
EUROPEAN JOURNAL OF CANCER, 1999, 35 (02) :309-315
[2]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[3]   Inhibition of telomerase activity by cisplatin in human testicular cancer cells [J].
Burger, AM ;
Double, JA ;
Newell, DR .
EUROPEAN JOURNAL OF CANCER, 1997, 33 (04) :638-644
[4]   The biology of replicative senescence [J].
Campisi, J .
EUROPEAN JOURNAL OF CANCER, 1997, 33 (05) :703-709
[5]   Aging and cancer: The double-edged sword of replicative senescence [J].
Campisi, J .
JOURNAL OF THE AMERICAN GERIATRICS SOCIETY, 1997, 45 (04) :482-488
[6]   Pt(II) complexes with different N-donor aromatic ligands for specific inhibition of telomerase [J].
Cavigiolio, G ;
Benedetto, L ;
Boccaleri, E ;
Colangelo, D ;
Viano, I ;
Osella, D .
INORGANICA CHIMICA ACTA, 2000, 305 (01) :61-68
[7]  
Faraoni I, 1997, CLIN CANCER RES, V3, P579
[8]   THE RNA COMPONENT OF HUMAN TELOMERASE [J].
FENG, JL ;
FUNK, WD ;
WANG, SS ;
WEINRICH, SL ;
AVILION, AA ;
CHIU, CP ;
ADAMS, RR ;
CHANG, E ;
ALLSOPP, RC ;
YU, JH ;
LE, SY ;
WEST, MD ;
HARLEY, CB ;
ANDREWS, WH ;
GREIDER, CW ;
VILLEPONTEAU, B .
SCIENCE, 1995, 269 (5228) :1236-1241
[9]   Inhibition of telomerase limits the growth of human cancer cells [J].
Hahn, WC ;
Stewart, SA ;
Brooks, MW ;
York, SG ;
Eaton, E ;
Kurachi, A ;
Beijersbergen, RL ;
Knoll, JHM ;
Meyerson, M ;
Weinberg, RA .
NATURE MEDICINE, 1999, 5 (10) :1164-1170
[10]  
Holt SE, 1996, MOL CELL BIOL, V16, P2932