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Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines

Oncogene volume 25, pages 503–511 (2006)Cite this article

Abstract

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 IC50 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.

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Acknowledgements

This work was supported by grants from the National Nature Science Foundation of China (30400556, 20472117), 973 program (2004CB518801) and 985-II project in China.

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Authors and Affiliations

  1. State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, China

    J-M Zhou, X-F Zhu, R Deng, Y-P Mei, Y Wang, W-L Huang, Z-C Liu & Y-X Zeng

  2. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China

    Y-J Lu, Z-S Huang & L-Q Gu

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  1. J-M Zhou
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Correspondence to X-F Zhu, Z-S Huang or Y-X Zeng.

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Zhou, JM., Zhu, XF., Lu, YJ. et al. Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines. Oncogene 25, 503–511 (2006). https://doi.org/10.1038/sj.onc.1209067

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