Ishikawa Chie, Mori Naoki
Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.
Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa, 903-0213, Japan.
Invest New Drugs. 2021 Feb;39(1):111-121. doi: 10.1007/s10637-020-00996-1. Epub 2020 Sep 3.
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.
原发性渗出性淋巴瘤（PEL）由卡波西肉瘤相关疱疹病毒（KSHV）引起，表现为体腔中的淋巴瘤性渗出液，预后较差。抗疟疾药物青蒿琥酯具有抗肿瘤潜力。因此，我们旨在研究其对KSHV感染的PEL细胞系的作用。青蒿琥酯抑制PEL细胞的生长和活力，但其对外周血单个核细胞的作用不太明显。青蒿琥酯通过下调细胞周期蛋白D1/D2、细胞周期蛋白依赖性激酶2/6和c-Myc诱导G1期阻滞。青蒿琥酯增加活性氧和DNA损伤，但不影响KSHV潜伏和裂解基因的表达。它通过半胱天冬酶依赖性和非依赖性途径表现出细胞毒性，并降低Bcl-xL、生存素、X连锁凋亡抑制蛋白和细胞凋亡抑制蛋白1/2水平。此外，青蒿琥酯通过抑制IκB激酶和IκBα磷酸化以及JunB表达来抑制核因子κB和激活蛋白1。最后，青蒿琥酯治疗减轻了小鼠PEL的发展。我们的数据支持青蒿琥酯是一种治疗PEL的潜在药物。
