title: Triptolide decreases expression of latency-associated nuclear antigen 1 and reduces viral titers in Kaposi's sarcoma-associated and herpesvirus-related primary effusion lymphoma cells.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) can establish a life-long persistence in the host after primary infection and is associated with certain malignancies, which are resistant to conventional chemotherapeutic agents with a poor prognosis. Latency-associated nuclear antigen 1 (LANA1) encoded by KSHV is essential for segregation, replication and maintenance of viral genome. In addition, LANA1 upregulates the transcriptional activity of signal transducer and activator of transcription 3 (STAT3), which plays an important role in promoting survival of KSHV-associated primary effusion lymphoma (PEL) cells. Furthermore, LANA1 mediates transcriptional modulation of KSHV and host genome in host cells. In the present study, the antitumor effect of triptolide was assessed. CCK-8 assays were performed to demonstrate that the proliferations of PEL cells were efficiently inhibited by triptolide in a dose- and time-dependent manner. Flow cytometric results indicated that triptolide induced cell cycle arrest and apoptosis. Western blot results suggested that triptolide downregulated LANA1 expression and reduced half-life of LANA1 in the KSHV-infected malignant cells. Viral titer experiments indicated that triptolide treatment impaired the number of viral DNA copies and the production of virions in BCBL-1 cells. Triptolide also suppressed STAT3 activity and inhibited secretion of IL-6 in PEL cells. In a mouse xenograft model of primary effusion lymphoma by BCBL-1 cells, triptolide treatment significantly inhibited ascites formation and diffused organ infiltration. These results indicate that triptolide impairs the expression of LANA1 and shows antitumor activity against PEL in vitro and in vivo. Triptolide may be a potential agent for treatment of PEL.
authors.affiliation: Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Cong
authors.initials: C
authors.lastname: Long
authors.affiliation: Department of Pathology and Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Jingchao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D015536:Down-Regulation; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000821:virology; D019562:Viral Load / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000956:Antigens, Viral; D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D009687:Nuclear Proteins; D010616:Phenanthrenes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C109540:latency-associated nuclear antigen; C001899:triptolide