title: Diphenylene iodonium interferes with cell cycle progression and induces apoptosis by modulating NAD(P)H oxidase/ROS/cell cycle regulatory pathways in Burkitt's lymphoma cells.
abstract: Infection with Epstein-Barr virus (EBV) and its encoded latent membrane protein 1 (LMP1) play oncogenic roles in Burkitt's lymphoma (BL). Flow cytometry was used to measure cellular reactive oxygen species (ROS) concentrations, and cellular lactate generation and diphenylene iodonium (DPI) cytotoxicity were determined by analyzing lactate concentrations and cell viability. We also measured NAD(P)H oxidase (NOX) activity. Reverse transcriptase PCR and qPCR assays were used to analyze LMP1 levels, and protein expression was measured by immunoblotting. In the present study, EBV was able to induce NOX activity and ROS generation in the BL cells. Inhibition of NOX activity by DPI suppressed ROS levels and elevated lactate levels. DPI treatment first resulted in a G2-M phase cell cycle arrest and then induced significant apoptosis. Immunoblot analysis demonstrated that DPI suppressed the expression of c-Myc and Cdc25A within 6 h, which may have caused the cell cycle arrest. Collectively, these findings indicate a close relationship between EBV infection and NOX activation, permitting a deeper understanding of ROS inhibition in cell cycle regulation and providing a novel therapeutic target for BL treatment.
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, P.R. China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000473:pathology* / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000096:biosynthesis
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; C489427:MYC protein, human; D009861:Onium Compounds; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014763:Viral Matrix Proteins; D019344:Lactic Acid; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases