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Advances in Virus-Directed Therapeutics against Epstein-Barr Virus-Associated Malignancies.

Ghosh SK, Perrine SP, Faller DV - Adv Virol (2012)

Bottom Line: Furthermore, the prognosis of these tumors is invariably poor when EBV is present, compared to their EBV-negative counterparts.The physical presence of EBV in these tumors represents a potential "tumor-specific" target for therapeutic approaches.A major constraint to pharmacological intervention is the shift from lytic infection to a latent pattern of gene expression, which persists in those tumors associated with the virus.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.

ABSTRACT
Epstein-Barr virus (EBV) is the causal agent in the etiology of Burkitt's lymphoma and nasopharyngeal carcinoma and is also associated with multiple human malignancies, including Hodgkin's and non-Hodgkin's lymphoma, and posttransplantation lymphoproliferative disease, as well as sporadic cancers of other tissues. A causal relationship of EBV to these latter malignancies remains controversial, although the episomic EBV genome in most of these cancers is clonal, suggesting infection very early in the development of the tumor and a possible role for EBV in the genesis of these diseases. Furthermore, the prognosis of these tumors is invariably poor when EBV is present, compared to their EBV-negative counterparts. The physical presence of EBV in these tumors represents a potential "tumor-specific" target for therapeutic approaches. While treatment options for other types of herpesvirus infections have evolved and improved over the last two decades, however, therapies directed at EBV have lagged. A major constraint to pharmacological intervention is the shift from lytic infection to a latent pattern of gene expression, which persists in those tumors associated with the virus. In this paper we provide a brief account of new virus-targeted therapeutic approaches against EBV-associated malignancies.

No MeSH data available.


Related in: MedlinePlus

Cytotoxic activity of various HDACi in the presence of an anti-herpesvirus nucleoside analog prodrug, GCV. Three hundred thousand P3HR1 cells were exposed to either 40 μM GCV or vehicle, and the indicated concentrations of individual HDACi, in a 1 mL volume in 24-well plates, in triplicate. Seventy-two hrs later, 800 μL of the media was removed without disturbing the settled cells and 1 mL of fresh growth media containing GCV (40 μM) was added and the cells, which were cultured for another 72 hrs. HDACi studied included butyrate, valproate, apicidin, largazole and its analogs, MS275, oxamflatin, LBH589, SAHA, and Scriptaid. The number above the HDAC+GCV bar represents the percentage of cells surviving, relative to the cultures exposed to that particular HDAC inhibitor alone (assigned a value of 100%). Error bars represent standard deviation.
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Related In: Results  -  Collection


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fig2: Cytotoxic activity of various HDACi in the presence of an anti-herpesvirus nucleoside analog prodrug, GCV. Three hundred thousand P3HR1 cells were exposed to either 40 μM GCV or vehicle, and the indicated concentrations of individual HDACi, in a 1 mL volume in 24-well plates, in triplicate. Seventy-two hrs later, 800 μL of the media was removed without disturbing the settled cells and 1 mL of fresh growth media containing GCV (40 μM) was added and the cells, which were cultured for another 72 hrs. HDACi studied included butyrate, valproate, apicidin, largazole and its analogs, MS275, oxamflatin, LBH589, SAHA, and Scriptaid. The number above the HDAC+GCV bar represents the percentage of cells surviving, relative to the cultures exposed to that particular HDAC inhibitor alone (assigned a value of 100%). Error bars represent standard deviation.

Mentions: In vitro studies have demonstrated that HDACi are potent antiproliferative agents that cause cell-cycle arrest, apoptosis and/or differentiation of tumors [86, 87]. Furthermore, their preferential cytotoxic activity on tumor cells over normal cells suggested potential anticancer therapeutic application. In recent years, a number of HDACi have been tested in clinical trials. In addition, efforts have been made to develop more potent, or more HDAC class selective, HDACi. Although HDACi as a class are well-known inducers of EBV lytic-phase gene expression [88], only butyrate and valproic acid have been tested for their activity in treating EBV malignancies [70, 76, 77]. We have recently completed studies to test a variety of HDACi of different chemical classes, including some new and highly potent compounds, for their ability to sensitize EBV-lymphoma cells to anti-herpesvirus drugs. The HDACi studied included short-chain fatty acids (butyrate, valproate), hydroxamic acids (SAHA, oxamflatin, LBH589, scriptaid, PDX101), benzamide (MS275), a cyclic tetrapeptide (apicidin), and largazoles (originally isolated from marine cyanobacterium). With the exception of SAHA and PXD101, all of the other HDACi produced sensitization to GCV, and the combination caused cytotoxicity in EBV+ lymphoma cells (when used as a single agent, PDX101 itself exerted a strong cytotoxic effect on the cells [89, 90]). LBH589, MS275, and synthetic largazole derivatives were 104 to 105 times more potent in killing EBV+ lymphoma cells in presence of GCV, compared to sodium butyrate (Figure 2). The effective concentration of LBH589 was in the range of 50–100 nM, MS275 at 200–500 nM, and largazoles at 100–200 nM. The effectiveness of these HDAC-inhibitory (HDACi) compounds at such low concentrations makes them potentially applicable as sensitizers to antiviral therapeutics for the treatment of EBV-associated lymphomas. Furthermore, butyrate and LBH589 were also found to potently sensitize another BL cell line (Daudi) and a lymphoblastoid cell line (JY) (Figure 3). These findings therefore suggest that that these new and potent HDACi may provide alternative therapeutic options to butyrate, in combination with nucleoside antiviral agents, for the treatment of EBV-associated tumors.


Advances in Virus-Directed Therapeutics against Epstein-Barr Virus-Associated Malignancies.

Ghosh SK, Perrine SP, Faller DV - Adv Virol (2012)

Cytotoxic activity of various HDACi in the presence of an anti-herpesvirus nucleoside analog prodrug, GCV. Three hundred thousand P3HR1 cells were exposed to either 40 μM GCV or vehicle, and the indicated concentrations of individual HDACi, in a 1 mL volume in 24-well plates, in triplicate. Seventy-two hrs later, 800 μL of the media was removed without disturbing the settled cells and 1 mL of fresh growth media containing GCV (40 μM) was added and the cells, which were cultured for another 72 hrs. HDACi studied included butyrate, valproate, apicidin, largazole and its analogs, MS275, oxamflatin, LBH589, SAHA, and Scriptaid. The number above the HDAC+GCV bar represents the percentage of cells surviving, relative to the cultures exposed to that particular HDAC inhibitor alone (assigned a value of 100%). Error bars represent standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303631&req=5

fig2: Cytotoxic activity of various HDACi in the presence of an anti-herpesvirus nucleoside analog prodrug, GCV. Three hundred thousand P3HR1 cells were exposed to either 40 μM GCV or vehicle, and the indicated concentrations of individual HDACi, in a 1 mL volume in 24-well plates, in triplicate. Seventy-two hrs later, 800 μL of the media was removed without disturbing the settled cells and 1 mL of fresh growth media containing GCV (40 μM) was added and the cells, which were cultured for another 72 hrs. HDACi studied included butyrate, valproate, apicidin, largazole and its analogs, MS275, oxamflatin, LBH589, SAHA, and Scriptaid. The number above the HDAC+GCV bar represents the percentage of cells surviving, relative to the cultures exposed to that particular HDAC inhibitor alone (assigned a value of 100%). Error bars represent standard deviation.
Mentions: In vitro studies have demonstrated that HDACi are potent antiproliferative agents that cause cell-cycle arrest, apoptosis and/or differentiation of tumors [86, 87]. Furthermore, their preferential cytotoxic activity on tumor cells over normal cells suggested potential anticancer therapeutic application. In recent years, a number of HDACi have been tested in clinical trials. In addition, efforts have been made to develop more potent, or more HDAC class selective, HDACi. Although HDACi as a class are well-known inducers of EBV lytic-phase gene expression [88], only butyrate and valproic acid have been tested for their activity in treating EBV malignancies [70, 76, 77]. We have recently completed studies to test a variety of HDACi of different chemical classes, including some new and highly potent compounds, for their ability to sensitize EBV-lymphoma cells to anti-herpesvirus drugs. The HDACi studied included short-chain fatty acids (butyrate, valproate), hydroxamic acids (SAHA, oxamflatin, LBH589, scriptaid, PDX101), benzamide (MS275), a cyclic tetrapeptide (apicidin), and largazoles (originally isolated from marine cyanobacterium). With the exception of SAHA and PXD101, all of the other HDACi produced sensitization to GCV, and the combination caused cytotoxicity in EBV+ lymphoma cells (when used as a single agent, PDX101 itself exerted a strong cytotoxic effect on the cells [89, 90]). LBH589, MS275, and synthetic largazole derivatives were 104 to 105 times more potent in killing EBV+ lymphoma cells in presence of GCV, compared to sodium butyrate (Figure 2). The effective concentration of LBH589 was in the range of 50–100 nM, MS275 at 200–500 nM, and largazoles at 100–200 nM. The effectiveness of these HDAC-inhibitory (HDACi) compounds at such low concentrations makes them potentially applicable as sensitizers to antiviral therapeutics for the treatment of EBV-associated lymphomas. Furthermore, butyrate and LBH589 were also found to potently sensitize another BL cell line (Daudi) and a lymphoblastoid cell line (JY) (Figure 3). These findings therefore suggest that that these new and potent HDACi may provide alternative therapeutic options to butyrate, in combination with nucleoside antiviral agents, for the treatment of EBV-associated tumors.

Bottom Line: Furthermore, the prognosis of these tumors is invariably poor when EBV is present, compared to their EBV-negative counterparts.The physical presence of EBV in these tumors represents a potential "tumor-specific" target for therapeutic approaches.A major constraint to pharmacological intervention is the shift from lytic infection to a latent pattern of gene expression, which persists in those tumors associated with the virus.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.

ABSTRACT
Epstein-Barr virus (EBV) is the causal agent in the etiology of Burkitt's lymphoma and nasopharyngeal carcinoma and is also associated with multiple human malignancies, including Hodgkin's and non-Hodgkin's lymphoma, and posttransplantation lymphoproliferative disease, as well as sporadic cancers of other tissues. A causal relationship of EBV to these latter malignancies remains controversial, although the episomic EBV genome in most of these cancers is clonal, suggesting infection very early in the development of the tumor and a possible role for EBV in the genesis of these diseases. Furthermore, the prognosis of these tumors is invariably poor when EBV is present, compared to their EBV-negative counterparts. The physical presence of EBV in these tumors represents a potential "tumor-specific" target for therapeutic approaches. While treatment options for other types of herpesvirus infections have evolved and improved over the last two decades, however, therapies directed at EBV have lagged. A major constraint to pharmacological intervention is the shift from lytic infection to a latent pattern of gene expression, which persists in those tumors associated with the virus. In this paper we provide a brief account of new virus-targeted therapeutic approaches against EBV-associated malignancies.

No MeSH data available.


Related in: MedlinePlus