Increasing sensitivity to arsenic trioxide-induced apoptosis by altered telomere state.
In this work, we investigated the synergic effects between low-dose arsenic trioxide and diethyloxadicarbocyanine (DODC), a telomerase inhibitor, on cell apoptosis. Results revealed that low-dose arsenic could block cell cycle arrest at the G2/M phase and induce apoptosis, whereas DODC could block cell cycle arrest at the G0/G1 phase but not induce apoptosis. However, cells pretreated with DODC showed greater sensitivity to arsenic than untreated cells. The percentage of apoptosis produced by combination treatment with the two agents increased and that was similar to the effect of high-dose arsenic treatment alone. Further studies showed that DODC alone could induce hairpin G-quadruplex formation and inhibit telomerase activity in a dose-dependent manner. Compared with HT1080 cells, 293 cells were more sensitive to cell growth inhibition and apoptosis and were less sensitivity to telomerase activity. These results indicate that DODC can synergistically enhance the apoptosis induced by arsenic, suggesting the increased cell senescence in response to arsenic is induced by an altered telomere state rather than by a loss of telomerase. Thus clinical application of combination treatment with arsenic and telomerase inhibitor may have potential in cancer therapy.
Zhang
Yan
Y
Institute of Biophysics, Academia Sinica, Chaoyang District, 100101 Beijing, PR China.
Cao
En-Hua
EH
Liang
Xiao-Qiu
XQ
Qin
Jing-Fen
JF
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000502:physiology
D001152:Arsenicals; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D010087:Oxides; D019098:Telomerase; D000077237:Arsenic Trioxide