The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production

Klass, Carmen M.; Krug, Laurie T.; Pozharskaya, Veronika P.; Offermann, Margaret K.

doi:10.1182/blood-2004-09-3569

Cited by 72 publications

(37 citation statements)

References 76 publications

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“…This antiviral effect likely results from the dependency of KSHV on the proteasome throughout the viral replicative cycle, which has been described in the context of other herpesvirus (40,41). Here, while Btz induced the expression of many KSHV lytic genes, the transcription of several key genes was affected negatively, indicating that the proteasome inhibition has gene-specific effects on viral lytic transcription.…”

Section: Btz-induced Apoptosis In Pel Is Mediated Via the Intrinsic Mmentioning

confidence: 74%

Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma

Bhatt¹,

Ashlock²,

Toomey³

et al. 2013

J. Clin. Invest.

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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.

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Section: Btz-induced Apoptosis In Pel Is Mediated Via the Intrinsic Mmentioning

confidence: 74%

Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma

Bhatt¹,

Ashlock²,

Toomey³

et al. 2013

J. Clin. Invest.

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show abstract

“…The efficacy of antiviral treatment can potentially be improved if PEL cells can be induced to enter the lytic phase of viral replication, as the majority of antiviral drugs are most effective in the lytic phase. In vitro data have suggested that the combination of the antiseizure medication valproate, which induces lytic replication, with either ganciclovir or foscarnet can bring about apoptosis of infected cells [64].…”

Section: Treatmentmentioning

confidence: 99%

Primary Effusion Lymphoma

2007

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“…In addition, VPA can induce the demethylation of exogenous plasmid DNA in mammalian cells (26). VPA has been previously shown to activate lytic viral gene expression in cells infected with human cytomegalovirus or KSHV (27)(28)(29). We therefore reasoned that VPA treatment might induce lytic EBV gene expression in latently infected host cells and/or enhance the ability of chemotherapy to activate lytic EBV gene expression in EBV-infected tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Valproic Acid Enhances the Efficacy of Chemotherapy in EBV-Positive Tumors by Increasing Lytic Viral Gene Expression

2006

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EBV infection in tumor cells is generally restricted to the latent forms of viral infection. Switching the latent form of viral infection into the lytic form may induce tumor cell death. We have previously reported that certain chemotherapy agents can increase the amount of lytic viral gene expression in EBV-positive tumor cells. In this report, we have explored the potential utility of valproic acid (VPA), an anti-seizure drug that also has strong histone deacetylase inhibitory activity, for activating lytic viral gene expression in EBVpositive tumors. Although VPA treatment alone induced only a modest increase in the level of lytic viral gene expression, it strongly enhanced the ability of chemotherapeutic agents to induce lytic EBV gene expression in EBV-positive epithelial and lymphoid cells in vitro. Furthermore, VPA enhanced cell killing in vitro by chemotherapeutic agents in lymphoblastoid cells and gastric cells (AGS) containing wild-type EBV. In contrast, VPA did not enhance the cytotoxicity of chemotherapy in lymphoblastoid cells containing a lytic-defective (BZLF1-knockout) form of EBV or in EBV-negative AGS cells. Finally, we found that the combination of VPA and chemotherapy was significantly more effective in inhibiting EBVdriven lymphoproliferative disease in severe combined immunodeficient mice than chemotherapy alone. These results suggest that VPA could potentiate the efficacy of chemotherapy for EBV-positive tumors in patients.

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The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production

Cited by 72 publications

References 76 publications

Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma

Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma

Primary Effusion Lymphoma

Valproic Acid Enhances the Efficacy of Chemotherapy in EBV-Positive Tumors by Increasing Lytic Viral Gene Expression

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