title: Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma.
abstract: Primary effusion lymphoma (PEL) is a rare form of aggressive B cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Current chemotherapy approaches result in dismal outcomes, and there is an urgent need for new PEL therapies. Previously, we established, in a direct xenograft model of PEL-bearing immune-compromised mice, that treatment with the proteasome inhibitor, bortezomib (Btz), increased survival relative to that after treatment with doxorubicin. Herein, we demonstrate that the combination of Btz with the histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA, also known as vorinostat) potently reactivates KSHV lytic replication and induces PEL cell death, resulting in significantly prolonged survival of PEL-bearing mice. Importantly, Btz blocked KSHV late lytic gene expression, terminally inhibiting the full lytic cascade and production of infectious virus in vivo. Btz treatment led to caspase activation and induced DNA damage, as evidenced by the accumulation of phosphorylated γH2AX and p53. The addition of SAHA to Btz treatment was synergistic, as SAHA induced early acetylation of p53 and reduced interaction with its negative regulator MDM2, augmenting the effects of Btz. The eradication of KSHV-infected PEL cells without increased viremia in mice provides a strong rationale for using the proteasome/HDAC inhibitor combination therapy in PEL.
authors: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Shruti
authors: S
authors: Bhatt
authors: Brittany M
authors: BM
authors: Ashlock
authors: Ngoc L
authors: NL
authors: Toomey
authors: Luis A
authors: LA
authors: Diaz
authors: Enrique A
authors: EA
authors: Mesri
authors: Izidore S
authors: IS
authors: Lossos
authors: Juan Carlos
authors: JC
authors: Ramos
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D057809:HEK293 Cells; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000821:virology; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000008:administration & dosage; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D017735:Virus Latency / Q000187:drug effects; D014779:Virus Replication; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C489427:MYC protein, human; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; D000069286:Bortezomib
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