Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma

Shruti Bhatt, Brittany M. Ashlock, Ngoc L. Toomey, Luis A. Diaz, Enrique A Mesri, Izidore Lossos, Juan Carlos Ramos

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Abstract

Primary effusion lymphoma (PEL) is a rare form of aggressive B cell lymphoma caused by Kaposi's sarcomaassociated 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 PELbearing 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 KSHVinfected PEL cells without increased viremia in mice provides a strong rationale for using the proteasome/HDAC inhibitor combination therapy in PEL.

Original languageEnglish
Pages (from-to)2616-2628
Number of pages13
JournalJournal of Clinical Investigation
Volume123
Issue number6
DOIs
StatePublished - Jun 3 2013

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Primary Effusion Lymphoma
Histone Deacetylase Inhibitors
Proteasome Endopeptidase Complex
Herpesviridae
Therapeutics
Proteasome Inhibitors
Viremia
B-Cell Lymphoma
Acetylation
Caspases
Heterografts
Doxorubicin
DNA Damage
Bortezomib
Cell Death
Viruses
Gene Expression
Drug Therapy
Acids

ASJC Scopus subject areas

  • Medicine(all)

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Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. / Bhatt, Shruti; Ashlock, Brittany M.; Toomey, Ngoc L.; Diaz, Luis A.; Mesri, Enrique A; Lossos, Izidore; Carlos Ramos, Juan.

In: Journal of Clinical Investigation, Vol. 123, No. 6, 03.06.2013, p. 2616-2628.

Research output: Contribution to journalArticle

Bhatt, Shruti ; Ashlock, Brittany M. ; Toomey, Ngoc L. ; Diaz, Luis A. ; Mesri, Enrique A ; Lossos, Izidore ; Carlos Ramos, Juan. / Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 6. pp. 2616-2628.
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