Abstract
BackgroundKaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans.Methodology/Principal FindingsUsing this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice.Conclusion/SignificanceThese results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.
Highlights
Infection with Kaposi sarcoma associated herpesvirus (KSHV) ( known as Human Herpesvirus Type 8 (HHV-8)) [1], is linked to all forms of Kaposi sarcoma, primary effusion lymphoma (PEL) [2,3,4], and some forms of multicentric Castelman’s disease (MCD) [5,6]
In human T cell leukemia virus type 1 (HTLV-1) associated adult T-cell leukemia (ATL) [55], we have shown that the combination of arsenic and IFN degrades the viral oncoprotein Tax, cures murine ATL and induces a high rate of response when combined with AZT in human chronic ATL [ 56–63]
In this report, using the preclinical NOD/SCID mouse model, we demonstrate that the combination of arsenic and IFN inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, viral FLICE inhibitory protein (v-FLIP) and viral cyclin (v-Cyc) in primary effusion lymphomas (PEL) cells derived from malignant ascites
Summary
Infection with Kaposi sarcoma associated herpesvirus (KSHV) ( known as Human Herpesvirus Type 8 (HHV-8)) [1], is linked to all forms of Kaposi sarcoma, primary effusion lymphoma (PEL) [2,3,4], and some forms of multicentric Castelman’s disease (MCD) [5,6]. PEL is a monoclonal/ oligoclonal, rare, aggressive and body cavity-based B-cell lymphoma, accounting for approximately 3% of AIDS-related lymphomas [7,8] This unusual lymphoproliferative disorder is divided into classical and solid variants. Methodology/Principal Findings: Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. This combination decreases the peritoneal volume and synergistically increases survival of PEL mice. Conclusion/Significance: These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients
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