title: Caspase-3-dependent apoptosis of citreamicin ε-induced HeLa cells is associated with reactive oxygen species generation.
abstract: Citreamicins, members of the polycyclic xanthone family, are promising antitumor agents that are produced by Streptomyces species. Two diastereomers, citreamicin ε A (1) and B (2), were isolated from a marine-derived Streptomyces species. The relative configurations of these two diastereomers were determined using NMR spectroscopy and successful crystallization of citreamicin ε A (1). Both diastereomers showed potent cytotoxic activity against HeLa (cervical cancer) and HepG2 (hepatic carcinoma) cells with IC50 values ranging from 30 to 100 nM. The terminal deoxynucleotidyl transferase dUTP nick-end labeling assay confirmed that citreamicin ε A (1) induced cellular apoptosis, and Western blot analysis showed that apoptosis occurred via activation of caspase-3. The 2,7-dichlorofluorescein diacetate assay indicated that citreamicin ε substantially increased the intracellular concentration of reactive oxygen species (ROS). To confirm the hypothesis that citreamicin ε induced apoptosis through an increase in the intracellular ROS concentration, the oxidized products, oxicitreamicin ε A (3) and B (4), were obtained from a one-step reaction catalyzed by Ag2O. These products, with a reduced capacity to increase the intracellular ROS concentration, exhibited a significantly weakened cytotoxicity in both HeLa and HepG2 cells compared with that of citreamicin ε A (1) and B (2).
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong SAR, China.
authors.forename: Ling-Li
authors.initials: LL
authors.lastname: Liu
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: He
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Han
authors.forename: Yong-Xin
authors.initials: YX
authors.lastname: Li
authors.forename: Jia-Liang
authors.initials: JL
authors.lastname: Zhong
authors.forename: Xian-Rong
authors.initials: XR
authors.lastname: Guo
authors.forename: Xi-Xiang
authors.initials: XX
authors.lastname: Zhang
authors.forename: Kam Ming
authors.initials: KM
authors.lastname: Ko
authors.forename: Pei-Yuan
authors.initials: PY
authors.lastname: Qian
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010080:Oxazoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010080:Oxazoles; D017382:Reactive Oxygen Species; C064661:citreamicin eta; D053148:Caspase 3