title: A newly identified berberine derivative induces cancer cell senescence by stabilizing endogenous G-quadruplexes and sparking a DNA damage response at the telomere region.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Yun-Xia
authors.initials: YX
authors.lastname: Xiong
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Hua-Fei
authors.initials: HF
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lv
authors.affiliation: Department of Medical Science, Shunde Polytechnic, Foshan 528333, P.R.China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Shi-Ke
authors.initials: SK
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China.
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D016588:Anticarcinogenic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001599:Berberine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D054856:G-Quadruplexes / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D016588:Anticarcinogenic Agents; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D001599:Berberine
keywords: DNA damage; berberine derivative; cancer cell senescence; telomeric G-quadruplex