Effects of cationic porphyrins as G-quadruplex interactive agents in humantumor cells

Citation
E. Izbicka et al., Effects of cationic porphyrins as G-quadruplex interactive agents in humantumor cells, CANCER RES, 59(3), 1999, pp. 639-644
Citations number
29
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
59
Issue
3
Year of publication
1999
Pages
639 - 644
Database
ISI
SICI code
0008-5472(19990201)59:3<639:EOCPAG>2.0.ZU;2-E
Abstract
A series of cationic porphyrins has been identified as G-quadruplex interac tive agents (QIAs) that stabilize telomeric G-quadruplex DNA and thereby in hibit human telomerase; 50% inhibition of telomerase activity was achieved in HeLa cell-free extract at porphyrin concentrations in the range greater than or equal to 50 mu M. Cytotoxicity of the porphyrins in vitro was asses sed in normal human cells (fibroblast and breast) and human tumor cells rep resenting models selected for high telomerase activity and short telomeres (breast carcinoma, prostate, and lymphoma). In general, the cytotoxicity (E C50, effective concentration for 50% inhibition of cell proliferation) agai nst normal and tumor cells was >50 mu M. The porphyrins were readily absorb ed into tumor cell nuclei in culture. Inhibition of telomerase activity in MCF7 cells by subcytotoxic concentrations of TMPyP4 showed time and concent ration dependence at 1-100 mu M TMPyP4 over 15 days in culture (10 populati on doubling times). The inhibition of telomerase activity was paralleled by a cell growth arrest in G(2)-M. These results suggest that relevant biolog ical effects of porphyrins can be achieved at concentrations that do not ha ve general cytotoxic effects on cells. Moreover, the data support the conce pt that a rational, structure-based approach is possible to design novel te lomere-interactive agents with application to a selective and specific anti cancer therapy.