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Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications

Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and nontreatable malignancy commonly found in AIDS patients. In this study, we performed a high-throughput screening of 3,731 characterized compounds and identified cyta...

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Autores principales: Gruffaz, Marion, Zhou, Shenghua, Vasan, Karthik, Rushing, Teresa, Michael, Qing Liu, Lu, Chu, Jung, Jae U., Gao, Shou-Jiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941074/
https://www.ncbi.nlm.nih.gov/pubmed/29739902
http://dx.doi.org/10.1128/mBio.00756-18
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author Gruffaz, Marion
Zhou, Shenghua
Vasan, Karthik
Rushing, Teresa
Michael, Qing Liu
Lu, Chu
Jung, Jae U.
Gao, Shou-Jiang
author_facet Gruffaz, Marion
Zhou, Shenghua
Vasan, Karthik
Rushing, Teresa
Michael, Qing Liu
Lu, Chu
Jung, Jae U.
Gao, Shou-Jiang
author_sort Gruffaz, Marion
collection PubMed
description Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and nontreatable malignancy commonly found in AIDS patients. In this study, we performed a high-throughput screening of 3,731 characterized compounds and identified cytarabine, approved by the FDA for treating numerous types of cancer, as a potent inhibitor of KSHV-induced PEL. We showed the high efficacy of cytarabine in the growth inhibition of various PEL cells by inducing cell cycle arrest and apoptosis. Cytarabine inhibited host DNA and RNA syntheses and therefore induced cellular cytotoxicity. Furthermore, cytarabine inhibited viral DNA and RNA syntheses and induced the rapid degradation of KSHV major latent protein LANA (latency-associated nuclear antigen), leading to the suppression of KSHV latent replication. Importantly, cytarabine effectively inhibited active KSHV replication and virion production in PEL cells. Finally, cytarabine treatments not only effectively inhibited the initiation and progression of PEL tumors but also induced regression of grown PEL tumors in a xenograft mouse model. Altogether, our study has identified cytarabine as a novel therapeutic agent for treating PEL as well as eliminating KSHV persistent infection.
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spelling pubmed-59410742018-05-15 Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications Gruffaz, Marion Zhou, Shenghua Vasan, Karthik Rushing, Teresa Michael, Qing Liu Lu, Chu Jung, Jae U. Gao, Shou-Jiang mBio Research Article Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and nontreatable malignancy commonly found in AIDS patients. In this study, we performed a high-throughput screening of 3,731 characterized compounds and identified cytarabine, approved by the FDA for treating numerous types of cancer, as a potent inhibitor of KSHV-induced PEL. We showed the high efficacy of cytarabine in the growth inhibition of various PEL cells by inducing cell cycle arrest and apoptosis. Cytarabine inhibited host DNA and RNA syntheses and therefore induced cellular cytotoxicity. Furthermore, cytarabine inhibited viral DNA and RNA syntheses and induced the rapid degradation of KSHV major latent protein LANA (latency-associated nuclear antigen), leading to the suppression of KSHV latent replication. Importantly, cytarabine effectively inhibited active KSHV replication and virion production in PEL cells. Finally, cytarabine treatments not only effectively inhibited the initiation and progression of PEL tumors but also induced regression of grown PEL tumors in a xenograft mouse model. Altogether, our study has identified cytarabine as a novel therapeutic agent for treating PEL as well as eliminating KSHV persistent infection. American Society for Microbiology 2018-05-08 /pmc/articles/PMC5941074/ /pubmed/29739902 http://dx.doi.org/10.1128/mBio.00756-18 Text en Copyright © 2018 Gruffaz et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Gruffaz, Marion
Zhou, Shenghua
Vasan, Karthik
Rushing, Teresa
Michael, Qing Liu
Lu, Chu
Jung, Jae U.
Gao, Shou-Jiang
Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications
title Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications
title_full Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications
title_fullStr Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications
title_full_unstemmed Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications
title_short Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Replications
title_sort repurposing cytarabine for treating primary effusion lymphoma by targeting kaposi’s sarcoma-associated herpesvirus latent and lytic replications
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941074/
https://www.ncbi.nlm.nih.gov/pubmed/29739902
http://dx.doi.org/10.1128/mBio.00756-18
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