Targeting KSHV/HHV-8 latency with COX-2 selective inhibitor nimesulide: a potential chemotherapeutic modality for primary effusion lymphoma.

Academic Article

Abstract

  • The significance of inflammation in KSHV biology and tumorigenesis prompted us to examine the role of COX-2 in primary effusion lymphoma (PEL), an aggressive AIDS-linked KSHV-associated non-Hodgkin's lymphoma (NHL) using nimesulide, a well-known COX-2 specific NSAID. We demonstrate that (1) nimesulide is efficacious in inducing proliferation arrest in PEL (KSHV+/EBV-; BCBL-1 and BC-3, KSHV+/EBV+; JSC-1), EBV-infected (KSHV-/EBV+; Raji) and non-infected (KSHV-/EBV-; Akata, Loukes, Ramos, BJAB) high malignancy human Burkitt's lymphoma (BL) as well as KSHV-/EBV+ lymphoblastoid (LCL) cell lines; (2) nimesulide is selectively toxic to KSHV infected endothelial cells (TIVE-LTC) compared to TIVE and primary endothelial cells (HMVEC-d); (3) nimesulide reduced KSHV latent gene expression, disrupted p53-LANA-1 protein complexes, and activated the p53/p21 tumor-suppressor pathway; (4) COX-2 inhibition down-regulated cell survival kinases (p-Akt and p-GSK-3β), an angiogenic factor (VEGF-C), PEL defining genes (syndecan-1, aquaporin-3, and vitamin-D3 receptor) and cell cycle proteins such as cyclins E/A and cdc25C; (5) nimesulide induced sustained cell death and G1 arrest in BCBL-1 cells; (6) nimesulide substantially reduced the colony forming capacity of BCBL-1 cells. Overall, our studies provide a comprehensive molecular framework linking COX-2 with PEL pathogenesis and identify the chemotherapeutic potential of nimesulide in treating PEL.
  • Authors

    Published In

  • PLoS ONE  Journal
  • Keywords

  • Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Separation, Cell Survival, Cyclooxygenase 2 Inhibitors, Dose-Response Relationship, Drug, Flow Cytometry, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Viral, Herpesvirus 8, Human, Humans, Lymphoma, Primary Effusion, Sulfonamides, Time Factors, Tumor Suppressor Protein p53
  • Digital Object Identifier (doi)

    Author List

  • Paul AG; Sharma-Walia N; Chandran B
  • Start Page

  • e24379
  • Volume

  • 6
  • Issue

  • 9