title: Directional modification of chrysin for exerting apoptosis and enhancing significantly anti-cancer effects of 10-hydroxy camptothecin.
abstract: Chrysin, one of natural flavonoid compounds, has recently been found to possess anti-inflammatory, antiallergic and anticancer properties. To increase its anticancer effects, 5 chrysin derivates were synthesized on the base of DNA intercalator structure. The inhibiting effects of chrysin and its derivatives on cancer cells Hela, BGC823, MCF-7, HepG2, and normal cells HEK-293, were evaluated by MTT assays. 5-(2'-amino) phenyl-7-cyclohexanemethylchrysin (Ch-1), a unique chrysin derivate, killed all the cancer cells but kept above 60% survival rate in normal cells HEK-293 at 62.5μM. Treated with chrysin from 250μM to 500μM, those cells were still maintained above 60% survival rate. The result of circular dichroism spectra showed that Ch-1 could intercalate DNA while chrysin had no effects on DNA. Interestingly, Hela cells survival rates were 95% and 10%, after treated with 20μM and 30μM of Ch-1, respectively. Both intrinsic and extrinsic apoptotic pathway were identified in regulating the cell death caused by Ch-1 in Hela cells. p53, the upstream regulator of apoptotic pathway were extremely significantly up-regulated in Hela cells treated with 25μM Ch-1. Moreover, the inhibiting effects and apoptotic related proteins responses to Ch-1 on Hela cells were abolished after pre-treated with Pifithrin-α (Pft-α), a p53 inhibitor. So, p53-depedent apoptosis is the crucial factor governing the inhibiting effects of Ch-1 in Hela cells. Amazingly, Ch-1 at non-toxic concentration (2.5-10μM) enhanced significantly anti-cancer effect of 10-hydroxy camptothecin (HCPT) on Hela, BGC823, and MCF-7 cells.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Tang
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Fangling
authors.initials: F
authors.lastname: Ji
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Guo
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Occupational and Environmental Health, Dalian Medical University, Dalian 116044, China. Electronic address: liy76@yahoo.com.
authors.forename: Yachen
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China; School of Food and Environmental Science and Technology, Dalian University of Technology, Panjin 124221, China. Electronic address: biosci@dlut.edu.cn.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Bao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D016159:Tumor Suppressor Protein p53; C043561:chrysin; D004247:DNA; D002166:Camptothecin
keywords: 10-Hydroxy camptothecin; Apoptosis; Chrysin, 5-(2′-amino) phenyl-7-cyclohexanemethylchrysin (Ch-1); DNA intercalator; Synergy