Activation of lytic cycle of Epstein‐Barr virus by suberoylanilide hydroxamic acid leads to apoptosis and tumor growth suppression of nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV). We reported that suberoylanilide hydroxamic acid (SAHA) induced EBV lytic cycle in EBV-positive gastric carcinoma cells and mediated enhanced cell death. However, expression of EBV lytic proteins was thought to exert antiapoptotic effect in EBV-infected cells. Here, we examined the in vitro and in vivo effects of SAHA on EBV lytic cycle induction in NPC cells and investigated the cellular consequences. Micromolar concentrations of SAHA significantly induced EBV lytic cycle in EBV-positive NPC cells. Increased apoptosis and proteolytic cleavage of poly(ADP-ribose) polymerase and caspase-3, -7 and -9 in EBV-positive versus EBV-negative NPC cells were observed. More than 85% of NPC cells expressing immediate-early (Zta), early (BMRF1) or late (gp350/220) lytic proteins coexpressed cleaved caspase-3. Tracking of expression of EBV lytic proteins and cleaved caspase-3 over time demonstrated that NPC cells proceeded to apoptosis following EBV lytic cycle induction. Inhibition of EBV DNA replication and late lytic protein expression by phosphonoformic acid did not impact on SAHA's induced cell death in NPC, indicating that early rather than late phase of EBV lytic cycle contributed to the apoptotic effect. In vivo effects of SAHA on EBV lytic cycle induction and tumor growth suppression were also observed in NPC xenografts in nude mice. Taken together, our data indicated that activation of lytic cycle from latent cycle of EBV by SAHA leads to apoptosis and tumor growth suppression of NPC thereby providing experimental evidence for virus-targeted therapy against EBV-positive cancer.

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

“…Our laboratory has previously shown that SAHA could significantly induce viral lytic cycle in EBV-positive gastric carcinoma and NPC cells and mediates enhanced apoptosis (11,12). The lytic cycle induction and tumor growth suppression mediated by SAHA could also be observed in NPC xenografts established in nude mice (12).…”

“…Suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) is a HDAC inhibitor approved by FDA for the treatment of cutaneous T-cell lymphoma. It alters gene expression by histone acetylation and mediates various cellular effects, including cell differentiation, cell-cycle arrest, and apoptosis, in different cancer cell types (9)(10)(11)(12). Combination of bortezomib and SAHA (bortezomib/SAHA) was shown to be effective in the treatment of hematologic malignant cells such as multiple myeloma (13), mantle cell lymphoma (14), cutaneous T-cell lymphoma (15), and leukemia (16,17).…”

“…Proteasome and HDAC inhibitors were also reported to induce EBV lytic cycle in different EBV-associated malignancies and lead to specific therapeutic effects against the cancer cells (11,12,23,24). Bortezomib was reported to induce EBV lytic cycle in EBV-positive Burkitt lymphoma and gastric carcinoma cells (25).…”

“…Induction of EBV lytic cycle by bortezomib could activate the radioisotope [ 125 I]2 0 -fluoro-2 0 -deoxy-b-D-5-iodouracil-arabinofuranoside to selectively suppress the growth of Burkitt lymphoma xenografts in severe combined immunodeficient (SCID) mice (25). Our laboratory has previously shown that SAHA could significantly induce viral lytic cycle in EBV-positive gastric carcinoma and NPC cells and mediates enhanced apoptosis (11,12). The lytic cycle induction and tumor growth suppression mediated by SAHA could also be observed in NPC xenografts established in nude mice (12).…”

Epstein-Barr Virus (EBV) and the Effectiveness of Suberoylanilide Hydroxamic Acid (SAHA) as a Treatment for EBV Infection and Associated Cancers

“…29 This pathway results in cellular differentiation or apoptosis of cancerous prostate and nasopharyngeal cells in vitro and prevents tumor growth in vivo. 14 41 as well as human immunodeficiency virus (HIV) infections 42 and in models of Huntington's disease. 43 In HIV, the virus remains latent in CD4 + T-cells; this stage is not susceptible to highly active anti-retroviral therapy (HAART) and thus patients will exhibit a rebound in viral load following cessation of treatment.…”