Stabilization of Telomere DNA, and Mechanism of Apoptosis of Tumor Cells Induced by Ruthenium Complexes
Received date: 2013-10-25
Online published: 2014-01-14
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 21171070, 21371075), the Planned Item of Science and Technology of Guangdong Province (No. c1211220800571), the Natural Science Foundation of Guangdong Province and the Fundamental Research Funds for the Central Universities.
Telomerase is highly expressed in tumor cells, which has become an important target of anticancer drugs. Since many tumor cells were rich in G4-DNA, we investigated the capabilities of these two ruthenium complexes to stabilize G4-DNA. Two ruthenium(Ⅱ) complexes were synthesized and characterized via electrospray ionization-mass spectrometry. Since many tumor cells were rich in G4-DNA, we investigated the capabilities of these two ruthenium complexes to stabilize G4-DNA. The interactions of these compounds with G-quadruplex DNA have been studied by fluorescence spectroscopy and circular dichroism (CD) spectroscopy. The stabilization of quadruplex DNA to complex 2 was better than complex 1, and complex 2 can induce telomeric G-quadruplex to occur conformation transformation, while complex 1 cannot. The results showed that the interaction of ruthenium complexes with G-quadruplex DNA was related with the plane of ligand. A novel visual method has been developed for making a distinction between ct-DNA and HTG21 by our Ru complexes binding hemin to form the hemin-G-quadruplex DNAzyme. The results showed that in the presence of complex 1 or 2, HTG21 can fold into a G-quadruplex, but CT-DNA cannot form the G-quadruplex structure. The anticancer activities of these complexes were evaluated by using the MTT assay. Interestingly, the anti-tumor activity of complex 2 exhibited greater inhibition to HepG2 cells, suggesting the ruthenium complexes were much less toxic towards normal cells, and speculated that it targeted the telomeric G-quadruplex was play a role on anti-tumor effect. To further evaluate the characteristics of the death induced by complexes 1 and 2-treated cells staining with Hoechst is analyzed by fluorescence microscopy. These results indicated that complex 2 revealed antiproliferative activities by apoptosis. We also used PI staining and flow cytometry to assess whether the ruthenium complex 2 affected cell cycle progression in HepG2 cells. Complex 2 is a potential antitumor drugs that can induce cancer cell death by acting on cell cycle arrest in G1 phase and the formation of DNA fragments (apoptosis characteristics).
Key words： telomerase; G-quadruplex DNA; ruthenium(Ⅱ) complexes; anti-tumor activity
Liu Ying , Chen Xiaoman , Zhang Langqi , Sun Dongdong , Zhou Yanhui , Chen Lanmei , Liu Jie . Stabilization of Telomere DNA, and Mechanism of Apoptosis of Tumor Cells Induced by Ruthenium Complexes[J]. Acta Chimica Sinica, 2014 , 72(4) : 473 -480 . DOI: 10.6023/A13101092
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