RRC ID 19301
Author Mikami-Terao Y, Akiyama M, Yuza Y, Yanagisawa T, Yamada O, Kawano T, Agawa M, Ida H, Yamada H.
Title Antitumor activity of TMPyP4 interacting G-quadruplex in retinoblastoma cell lines.
Journal Exp. Eye Res.
Abstract To investigate the molecular mechanism of the antitumor activity of the cationic porphyrin 5, 10, 15, 20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) in retinoblastoma cell lines, Y79 and WERI-Rb1 cells were treated with TMPyP4 for 0-72 h, after which growth inhibition, modulation of the cell cycle and the induction of apoptosis were examined. In addition, the effect of TMPyP4 on the susceptibility to irradiation was evaluated in Y79 and WERI-Rb1 cells. In vitro telomeric repeat amplification protocol assay showed TMPyP4 (10-100 microM) directly blocked telomerase elongation, suggesting that TMPyP4 can form stable guanine (G)-quadruplexes in extending telomere repeats in substrate oligonucleotides. The antiproliferative activities of TMPyP4 assessed with the MTS assay and expressed in terms of IC(50): Y79 cells, 60 microM; WERI-Rb1 cells, 45 microM. Treatment with TMPyP4 at doses of 10, 20, 50 or 100 microM for 48 or 72 h significantly inhibited the growth of Y79 and WERI-Rb1 cells. Apoptosis, as assessed with CaspACE FITC-VAD-FMK, was induced by TMPyP4 in a dose-dependent manner. Induction of apoptosis by TMPyP4 was associated with increased expression of phosphorylated DNA damage response factor H2AX (Ser139), phosphorylated p53 (Ser46) protein and activation of mitogen-activated protein kinases in Y79 and WERI-Rb1 cells. Moreover, TMPyP4 significantly enhanced the susceptibility to irradiation in both cell lines. This study provides insight into the molecular mechanism of the antitumor effects of TMPyP4. G-quadruplex structure may be a potential therapeutic target in retinoblastoma.
Volume 89(2)
Pages 200-8
Published 2009-8
DOI 10.1016/j.exer.2009.03.008
PII S0014-4835(09)00071-2
PMID 19328784
MeSH Antineoplastic Agents / metabolism Antineoplastic Agents / pharmacology* Apoptosis / drug effects Apoptosis / radiation effects Cell Division / drug effects DNA Damage Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Enzyme Inhibitors / pharmacology G-Quadruplexes / drug effects* Histones / metabolism Humans Mitogen-Activated Protein Kinase Kinases / metabolism Phosphorylation / drug effects Porphyrins / metabolism Porphyrins / pharmacology* Retinal Neoplasms / genetics Retinal Neoplasms / metabolism Retinal Neoplasms / pathology* Retinoblastoma / genetics Retinoblastoma / metabolism Retinoblastoma / pathology* Telomerase / antagonists & inhibitors Tumor Cells, Cultured
IF 2.998
Times Cited 21
Human and Animal Cells Y79 (RCB1645) WERI-Rb-1 (RCB2146)