Binding of G-quadruplex-interactive agents to distinct G-quadruplexes induces different biological effects in MiaPaCa cells.
Our previous studies have demonstrated the preference of telomestatin for intramolecular, rather than the intermolecular, G-quadruplex structures, while TiMPyP4 has selectivity for intermolecular over intramolecular G-quadruplex structures. However, it was not clear whether the difference in the selectivity between two different G-quadruplex-interactive agents could determine the corresponding biological effects in cultured human tumor cells. Here we evaluated the biological effects of both TMPyP4 and telomestatin in the human pancreatic carcinoma cell line (MiaPaCa) using subtoxic and cytotoxic concentrations. The cytotoxicity of these agents against MiaPaCa cells is quite different, and the IC50 of telomestatin (0.5 microM) is about 100 times less than that of TMPyP4 (50 microM). At IC50 concentrations, TMPyP4 induced anaphase bridge formation in MiaPaCa cells, while telomestatin failed to induce anaphase bridge formation. At subtoxic concentrations, TMPyP4 induced MiaPaCa cell growth arrest, senescence, apoptosis, and telomere length shortening within 5 weeks, while similar biological effects were evident after 12 weeks following treatment with telomestatin. Our data suggest that binding of G-quadruplex-interactive agents to distinct G-quadruplexes could induce different biological effects in human cancer cells.
Liu
Weijun
W
College of Pharmacy, The University of Arizona, Tucson, Arizona 85724, USA.
Sun
Daekyu
D
Hurley
Laurence H
LH
D000705:Anaphase / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D010080:Oxazoles; D011166:Porphyrins; C431888:telomestatin; C021096:tetra(4-N-methylpyridyl)porphine