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

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 3; pp. 639 - 644
• Main Authors: IZBICKA, E, WHEELHOUSE, R. T, RAYMOND, E, DAVIDSON, K. K, LAWRENCE, R. A, SUN, D, WINDLE, B. E, HURLEY, L. H, VON HOFF, D. D
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.1999
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Biological and medical sciences; Breast Neoplasms - drug therapy; Cations; Cell Nucleus - metabolism; Chemotherapy; DNA - drug effects; DNA - metabolism; DNA, Neoplasm - drug effects; DNA, Neoplasm - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; G-Quadruplexes; HeLa Cells; Humans; Medical sciences; Models, Molecular; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Porphyrins - pharmacokinetics; Porphyrins - pharmacology; Porphyrins - toxicity; Telomerase - antagonists & inhibitors; Telomerase - metabolism; Tumor Cells, Cultured; Adenocarcinoma; Antineoplastic agent; Carcinoma; RNA-directed DNA polymerase; Prostate disease; Mitosis; Cytotoxicity; Telomere; Enzymatic activity; Lymphoproliferative syndrome; Cell cycle; Established cell line; G2 Phase; Malignant lymphoma; Mammary gland; Male genital diseases; Tumor cell; Human; Urinary system disease; Enzyme; Transferases; Enzyme inhibitor; Malignant hemopathy; Malignant tumor; In vitro; Biological activity; Mammary gland diseases; Nucleotidyltransferases; Porphyrin; Prostate
• ISSN: 0008-5472

A series of cationic porphyrins has been identified as G-quadruplex interactive agents (QIAs) that stabilize telomeric G-quadruplex DNA and thereby inhibit human telomerase; 50% inhibition of telomerase activity was achieved in HeLa cell-free extract at porphyrin concentrations in the range < or = 50 microM. Cytotoxicity of the porphyrins in vitro was assessed in normal human cells (fibroblast and breast) and human tumor cells representing models selected for high telomerase activity and short telomeres (breast carcinoma, prostate, and lymphoma). In general, the cytotoxicity (EC50, effective concentration for 50% inhibition of cell proliferation) against normal and tumor cells was > 50 microM. The porphyrins were readily absorbed into tumor cell nuclei in culture. Inhibition of telomerase activity in MCF7 cells by subcytotoxic concentrations of TMPyP4 showed time and concentration dependence at 1-100 microM TMPyP4 over 15 days in culture (10 population doubling times). The inhibition of telomerase activity was paralleled by a cell growth arrest in G2-M. These results suggest that relevant biological effects of porphyrins can be achieved at concentrations that do not have general cytotoxic effects on cells. Moreover, the data support the concept that a rational, structure-based approach is possible to design novel telomere-interactive agents with application to a selective and specific anticancer therapy.