Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines.
Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells. N'-(10H-Indolo [3,2-b] quinolin-11-yl)-N, N-dimethyl-propane-1,3-diamine (SYUIQ-5), (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC(50) for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.
Zhou
J-M
JM
State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou.
Zhu
X-F
XF
Lu
Y-J
YJ
Deng
R
R
Huang
Z-S
ZS
Mei
Y-P
YP
Wang
Y
Y
Huang
W-L
WL
Liu
Z-C
ZC
Gu
L-Q
LQ
Zeng
Y-X
YX
D000470:Alkaloids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D004247:DNA; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere
D000470:Alkaloids; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D011804:Quinolines; D050760:Cyclin-Dependent Kinase Inhibitor p27; C016712:quindoline; D006147:Guanine; D004247:DNA; D019098:Telomerase