The anti-malaria agent artesunate exhibits cytotoxic effects in primary effusion lymphoma
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PRECLINICAL STUDIES
The anti-malaria agent artesunate exhibits cytotoxic effects in primary effusion lymphoma Chie Ishikawa 1,2 & Naoki Mori 1 Received: 7 July 2020 / Accepted: 27 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Primary effusion lymphoma (PEL), caused by Kaposi’s sarcoma-associated herpesvirus (KSHV), presents as a lymphomatous effusion in body cavities and has a poor prognosis. The anti-malaria drug, artesunate, possesses anti-neoplastic potential. Therefore, we aimed to investigate its effect on KSHV-infected PEL cell lines. Artesunate inhibited cell growth and viability of PEL cells, but its effect on peripheral blood mononuclear cells was less pronounced. Artesunate induced G1 phase arrest by downregulating cyclin D1/D2, CDK2/6 and c-Myc. Artesunate increased reactive oxygen species and DNA damage, but did not affect the expression of latent and lytic genes of KSHV. It exhibited cytotoxicity through caspase-dependent and -independent pathways and reduced Bcl-xL, survivin, XIAP and c-IAP1/2 levels. Furthermore, artesunate suppressed NF-κB and AP-1 by inhibiting IκB kinase and IκBα phosphorylation as well as JunB expression. Finally, artesunate treatment attenuated PEL development in mice. Our data support that artesunate is a potential drug for PEL treatment. Keywords Primary effusion lymphoma . Kaposi’s sarcoma-associated herpesvirus . Artesunate . Reactive oxygen species . NF-κB . AP-1
Introduction Primary effusion lymphoma (PEL), caused by infection with Kaposi’s sarcoma-associated herpesvirus (KSHV), presents with serious lymphomatous effusions in body cavities in the absence of detectable tumor masses [1, 2]. This lymphoma develops in immunosuppressed individuals, such as human immunodeficiency virus (HIV)-infected individuals and those taking immunosuppressant drugs after undergoing organ transplantation [1, 2]. Implementation of combination antiretroviral therapy is recommended when treating PEL patients with HIV infection [1, 2]. PEL is treated with combination chemotherapeutic regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), but patient
* Naoki Mori [email protected] 1
Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan
2
Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
prognosis remains extremely poor, with a short survival time of 6 months to 1 year [1, 2]. Hence, there exists an urgent need to develop a combination therapy for immunological recovery from immunodeficiency and molecular-targeted therapies for the activated proliferation and survival signals for PEL. Artesunate, a semisynthetic analog of artemisinin originally developed for the treatment of malaria, possesses antineoplastic activity [3, 4]. Artemisinin and its derivatives have been shown to selectively kill neoplastic
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