title: Histone deacetylase inhibitor romidepsin induces efficient tumor cell lysis via selective down-regulation of LMP1 and c-myc expression in EBV-positive diffuse large B-cell lymphoma.
abstract: We investigated the role of the histone deacetylase inhibitor, romidepsin, in Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma with poor clinical outcomes. We used EBV-positive and EBV-negative DLBCL cell lines and generated two EBV-transfected cell lines, LY7/EBV and U2932/EBV. Romidepsin was cytotoxic to cultured EBV-positive cells via the activation of the caspase cascade. Moreover, in vivo mice xenograft models demonstrated the cytotoxicity of romidepsin to EBV-positive DLBCL cells. Romidepsin induced cytotoxicity via the reduction of LMP1 and c-myc expression in EBV-positive cells. Inhibiting either LMP1 or c-myc using small inhibitory RNAs caused partial cytotoxicity in EBV-positive Farage and U2932/EBV lines. The dual inhibition of LMP1 and c-myc showed a synergistic cytotoxic effect in EBV-positive cells similar in magnitude to that of romidepsin alone. In addition, either double blockade of LMP1 and c-myc activity or romidepsin single treatment activated EBV lytic cycle in EBV-positive cells. In conclusion, romidepsin exerts strong anti-tumor activity in EBV-positive DLBCL via the inhibition of both LMP1 and c-myc. Our findings indicate that romidepsin might be a promising treatment for EBV-positive DLBCL.
authors: Division of Hematology & Medical Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Republic of Korea; Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Republic of Korea.
authors: Dong-Yeop
authors: DY
authors: Shin
authors: Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Republic of Korea; Laboratory of Experimental Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors: Areumnuri
authors: A
authors: Kim
authors: Division of Hematology & Medical Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Republic of Korea.
authors: Hye Jin
authors: HJ
authors: Kang
authors: Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Republic of Korea; Laboratory of Experimental Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors: Sunhoo
authors: S
authors: Park
authors: Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Dong Wan
authors: DW
authors: Kim
authors: Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Republic of Korea; Laboratory of Experimental Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea. Electronic address: sslee@kirams.re.kr.
authors: Seung-Sook
authors: SS
authors: Lee
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D020031:Epstein-Barr Virus Infections / Q000473:pathology / Q000821:virology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000821:virology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D014763:Viral Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D056572:Histone Deacetylase Inhibitors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014763:Viral Matrix Proteins; C087123:romidepsin
keywords: Diffuse large B-cell lymphoma; Epstein–Barr virus; Latent membrane protein-1; Romidepsin; c-myc