title: Cordycepin enhances Epstein-Barr virus lytic infection and Epstein-Barr virus-positive tumor treatment efficacy by doxorubicin.
abstract: The consistent latent presence of Epstein-Barr virus (EBV) in tumor cells offers potential for virus-targeted therapies. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. In this study, we report that a natural small molecule compound, cordycepin, can induce lytic EBV infection in tumor cells. Subsequently, we demonstrate that cordycepin can enhance EBV reactivating capacity and EBV-positive tumor cell killing ability of low dose doxorubicin. The combination of cordycepin and doxorubicin phosphorylates CCAAT/enhancer binding protein β (C/EBPβ) through protein kinase C (PKC)-p38 mitogen activated protein kinases (p38 MAPK) signaling pathway, and C/EBPβ is required for the activation of lytic EBV infection. Most importantly, an in vivo experiment demonstrates that the combination of cordycepin and doxorubicin is more effective in inhibiting tumor growth in SCID mice than is doxorubicin alone. Our findings establish that cordycepin can enhance the efficacy of conventional chemotherapy for treatment of EBV-positive tumors.
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China; Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Yinping
authors.initials: Y
authors.lastname: Du
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China; Department of Basic Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Jieshi
authors.initials: J
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China; Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Du
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China; Department of Basic Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China; Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, China. Electronic address: whfeng@cau.edu.cn.
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Feng
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003839:Deoxyadenosines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D016513:Mice, SCID; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000472:pathogenicity; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D003839:Deoxyadenosines; D004317:Doxorubicin; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; C058120:cordycepin
keywords: Cordycepin; Doxorubicin; EBV-associated tumors; Epstein–Barr virus