RESUMO
Primary effusion lymphoma (PEL) is an aggressive B-cell malignancy without effective treatment, and caused by the infection of Kaposi's sarcoma-associated herpesvirus (KSHV), predominantly in its latent form. Previously we showed that the SUMO2-interacting motif within the viral latency-associated nuclear antigen (LANASIM) is essential for establishment and maintenance of KSHV latency. Here, we developed a luciferase based live-cell reporter system to screen inhibitors selectively targeting the interaction between LANASIM and SUMO2. Cambogin, a bioactive natural product isolated from the Garcinia genus (a traditional herbal medicine used for cancer treatment), was obtained from the reporter system screening to efficiently inhibit the association of SUMO2 with LANASIM, in turn reducing the viral episome DNA copy number for establishment and maintenance of KSHV latent infection at a low concentration (nM). Importantly, Cambogin treatments not only specifically inhibited proliferation of KSHV-latently infected cells in vitro, but also induced regression of PEL tumors in a xenograft mouse model. This study has identified Cambogin as a novel therapeutic agent for treating PEL as well as eliminating persistent infection of oncogenic herpesvirus.
Assuntos
Antineoplásicos/farmacologia , Linfoma de Efusão Primária/virologia , Terpenos/farmacologia , Latência Viral/efeitos dos fármacos , Animais , Antígenos Virais/efeitos dos fármacos , Antígenos Virais/metabolismo , Células HEK293 , Infecções por Herpesviridae/metabolismo , Herpesvirus Humano 8 , Humanos , Camundongos , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/efeitos dos fármacos , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An unsymmetrically protonated PN(3) -pincer complex in which ruthenium is coordinated by one nitrogen and two phosphorus atoms was employed for the selective generation of hydrogen from formic acid. Mechanistic studies suggest that the imine arm participates in the formic acid activation/deprotonation step. A long life time of 150â h with a turnover number over 1 million was achieved.