Telomerase inhibition is a specific early event in salvicine-treated human lung adenocarcinoma A549 cells.
The telomere and telomerase have been suggested as targets for anticancer drug discovery. However, the mechanisms by which conventional anticancer drugs affect these targets are currently unclear. The novel topoisomerase II inhibitor, salvicine, suppresses telomerase activity in leukemia HL-60 cells. To further determine whether this activity of salvicine is specific to the hematological tumor and distinct from those of other conventional anticancer agents, we studied its effects on telomere and telomerase in a solid lung carcinoma cell line, A549. Differences in telomerase inhibition and telomere erosion were observed between salvcine and other anticancer agents. All anticancer agents (except adriamycin) induced shortening of the telomere, which was identified independent of replication, but only salvicine inhibited telomerase activity in A549 cells under conditions of high concentration and short-term exposure. At the low concentration and long-term exposure mode, all the tested anticancer agents shortened the telomere and inhibited telomerase activity in the same cell line. Notably, salvicine inhibited telomerase activity more severely than the other agents examined. Moreover, the compound inhibited telomerase activity in A549 cells indirectly in a concentration- and time-dependent manner. Salvicine did not affect the expression of hTERT, hTP1, and hTR mRNA in A549 cells following 4 h of exposure. Okadaic acid protected telomerase from inhibition by salvicine. These results indicate specificity of salvicine and diversity of anticancer agents in the mechanism of interference with telomerase and the telomere system. Our data should be helpful for designing the study in the development of agents acting on telomere and/or telomerase.
Liu
Wei-Jun
WJ
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Zhang
Yong-Wei
YW
Shen
Ying
Y
Jiang
Jian-Fei
JF
Miao
Ze-Hong
ZH
Ding
Jian
J
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D009285:Naphthoquinones / Q000008:administration & dosage*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects / Q000648:ultrastructure; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009285:Naphthoquinones; C122096:salvicine; D019098:Telomerase