title: Exposure of CCRF-CEM cells to acridone derivative 8a triggers tumor death via multiple mechanisms.
abstract: A newly synthesized acridone derivative 8a shows potent antitumor activity against CCRF-CEM leukemia cells. Herein, the first proteomic study of 8a effects in CCRF-CEM cells was performed by 2D nano-LC-ESI-MS/MS to better understand the mechanisms of action of 8a. Data analyses based on PLGS, STRING, Cytoscape, and database for annotation, visualization, and integrated discovery identified 55 proteins that were differentially expressed in response to 8a exposure. Multiple cellular pathways were affected, including chromatin organization, energy metabolism, DNA repair, oxidative-stress, and apoptosis. The changes in protein expression were further verified for PKM2. Moreover, 8a lowered down the expression of HEX and PFK-1. Lactate production was decreased in 8a-treated cells, indicating suppression of glycolysis. The elevated XRCC6 and decreased histone expression levels suggested increased DNA damage in 8a-treated cells, which was confirmed by the increased γ-H2AX foci. Molecular docking of 8a with DNA demonstrated direct interactions of 8a with DNA through three hydrogen bonds and four π-π interactions, potentially explaining the mode of action that 8a damaged to DNA. The differential protein profiling and dysfunction of metabolic pathways induced by 8a provide novel insights into the potential action mechanisms of 8a.
authors: Department of Chemistry, Tsinghua University, Beijing, P. R. China.|The Key Laboratory of Tumor Metabolomics at Shenzhen, Shenzhen, P. R. China.
authors: Yini
authors: Y
authors: Wang
authors: The Key Laboratory of Tumor Metabolomics at Shenzhen, Shenzhen, P. R. China.|The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, P. R. China.
authors: Dan
authors: D
authors: Gao
authors: The Key Laboratory of Tumor Metabolomics at Shenzhen, Shenzhen, P. R. China.|The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, P. R. China.
authors: Bizhu
authors: B
authors: Chu
authors: The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, P. R. China.
authors: Chunmei
authors: C
authors: Gao
authors: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors: Deliang
authors: D
authors: Cao
authors: The Key Laboratory of Tumor Metabolomics at Shenzhen, Shenzhen, P. R. China.|The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, P. R. China.
authors: Hongxia
authors: H
authors: Liu
authors: The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen, P. R. China.|School of Medicine, Tsinghua University, Beijing, P. R. China.
authors: Yuyang
authors: Y
authors: Jiang
mesh_terms: D054831:Acridones / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D013058:Mass Spectrometry; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D054831:Acridones; C041300:acridone
keywords: 2D nano LC-MS; Acridone derivative 8a; Biomedicine; DNA damage; Energy metabolism; Oxidative stress