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      Nutlin-3 induces apoptosis, disrupts viral latency and inhibits expression of angiopoietin-2 in Kaposi sarcoma tumor cells.

      Cell Cycle

      Angiopoietin-2, biosynthesis, Animals, Apoptosis, drug effects, Cell Line, Tumor, Cell Proliferation, G1 Phase Cell Cycle Checkpoints, Herpesvirus 8, Human, physiology, Human Umbilical Vein Endothelial Cells, metabolism, Humans, Imidazoles, pharmacology, Mice, Mice, Nude, Piperazines, Proto-Oncogene Proteins c-mdm2, antagonists & inhibitors, Sarcoma, Kaposi, Xenograft Model Antitumor Assays, pathology, virology, Telomerase, Tumor Suppressor Protein p53, genetics, Virus Latency

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          Abstract

          Kaposi sarcoma (KS) tumors often contain a wild-type p53. However, the function of this tumor suppressor in KS tumor cells is inhibited by both MDM2 and latent nuclear antigen (LANA) of Kaposi sarcoma-associated herpes virus (KSHV). Here, we report that MDM2 antagonist Nutlin-3 efficiently reactivates p53 in telomerase-immortalized human umbilical vein endothelial cells (TIVE) that had been malignantly transformed by KSHV as well as in KS tumor cells. Reactivation of p53 results in a G 1 cell cycle arrest, leading to inhibition of proliferation and apoptosis. Nutlin-3 inhibits the growth of "KS-like" tumors resulting from xenografted TIVE-KSHV cells in nude mice. In addition, Nutlin-3 strongly inhibits expression of the pro-angiogenic and pro-inflammatory cytokine angiopoietin-2 (Ang-2). It also disrupts viral latency by inducing expression of KSHV lytic genes. These results suggest that Nutlin-3 might serve as a novel therapy for KS.

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          Author and article information

          Journal
          22421142
          3350880
          10.4161/cc.19756

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