A newly identified berberine derivative induces cancer cell senescence by stabilizing endogenous G-quadruplexes and sparking a DNA damage response at the telomere region
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Yun-Xia Xiong1, Hua-Fei Su1, Peng Lv1, Yan Ma2, Shi-Ke Wang1, Hui Miao1, Hui-Yun Liu1, Jia-Heng Tan1, Tian-Miao Ou1, Lian-Quan Gu1, Zhi-Shu Huang1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China
2Department of Medical Science, Shunde Polytechnic, Foshan 528333, P.R.China
Zhi-Shu Huang, e-mail: firstname.lastname@example.org
Tian-Miao Ou, e-mail: email@example.com
Keywords: berberine derivative, telomeric G-quadruplex, DNA damage, cancer cell senescence
Received: June 16, 2015 Accepted: September 28, 2015 Published: October 08, 2015
The guanine-rich sequences are able to fold into G-quadruplexes in living cells, making these structures promising anti-cancer drug targets. In the current study, we identified a small molecule, Ber8, from a series of 9-substituted berberine derivatives and found that it could induce acute cell growth arrest and senescence in cancer cells, but not in normal fibroblasts. Further analysis revealed that the cell growth arrest was directly associated with apparent cell cycle arrest, cell senescence, and profound DNA damage at the telomere region. Significantly, our studies also provided evidence that Ber8 could stabilize endogenous telomeric G-quadruplexes structures in cells. Ber8 could then induce the delocalization of TRF1 and POT1 from the telomere accompanied by a rapid telomere uncapping. These results provide compelling insights into direct binding of telomeric G-quadruplexes and might contribute to the development of more selective, effective anticancer drugs.
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