title: Application of metabolomics to investigate the antitumor mechanism of flavopiridol in MCF-7 breast cancer cells.
abstract: Flavopiridol is reported to have potent antitumor effects by inhibition of cyclin-dependent kinases (CDKs). However, most studies of flavopiridol focus on specific genes and kinases, so the antitumor mechanism needs further elucidation at the metabolic level. In the present study, an UPLC/Q-TOF MS metabolomics approach was used to investigate its antiproliferative effects on MCF-7 breast cancer cells. Comparing flavopiridol-treated MCF-7 cells with vehicle control, 21 potential biomarkers involved in five metabolism pathways were identified. Two pathways involving glutathione metabolism and glycerophospholipid metabolism showed that glutathione (GSH) and phosphatidylcholines (PCs) levels were reduced while their oxidized products oxidized glutathione (GSSG) and lysophosphatidylcholines (LysoPCs) were greatly increased. Further investigation showed an apparent accumulation of reactive oxygen species (ROS) and a decrease in mitochondrial membrane potential (MMP). Thus, we suggest that oxidative stress was provoked in MCF-7 cells to reduce the GSH and PCs levels and cause mitochondria lesions. Moreover, cell cycle analysis showed that flavopiridol blocked cells at G1 stage, which was consistent with the depletion of spermidine and spermine that are believed to promote cancer progression. Taking these together, we concluded that flavopiridol could induce oxidative stress and cell cycle arrest, which finally lead to cell apoptosis in MCF-7 cells. This study provides a new strategy for studying the antitumor mechanism of flavopiridol, which could be used for its further improvement and application.
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China; State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Shao
authors.affiliation: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China. Electronic address: danielle1023@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China.
authors.forename: Yini
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Neptunus Pharmaceutical Technology Center, Shenzhen 518057, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China; State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China. Electronic address: liuhx@sz.tsinghua.edu.cn.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics / Q000379:methods*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D025341:Principal Component Analysis
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib
keywords: Antitumor mechanism; Cell cycle arrest; Flavopiridol; Metabolomics; Oxidative stress