Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
mBio. 2018 May 8;9(3):e00756-18. doi: 10.1128/mBio.00756-18.
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. Primary effusion lymphoma is an aggressive malignancy caused by Kaposi's sarcoma-associated herpesvirus. The outcome of primary effusion lymphoma is dismal without specific treatment. Through a high-throughput screening of characterized compounds, we identified an FDA-approved compound, cytarabine, as a potent inhibitor of primary effusion lymphoma. We showed that cytarabine induced regression of PEL tumors in a xenograft mouse model. Cytarabine inhibited host and viral DNA and RNA syntheses, resulting in the induction of cytotoxicity. Of interest, cytarabine induced the degradation of KSHV major latent protein LANA, hence suppressing KSHV latent replication, which is required for PEL cell survival. Furthermore, cytarabine inhibited KSHV lytic replication program, preventing virion production. Our findings identified cytarabine as a novel therapeutic agent for treating PEL as well as for eliminating KSHV persistent infection. Since cytarabine is already approved by the FDA, it might be an ideal candidate for repurposing for PEL therapy and for further evaluation in advanced clinical trials.
致癌性卡波济肉瘤相关疱疹病毒 (KSHV) 是原发性渗出性淋巴瘤 (PEL) 的病因，PEL 是一种侵袭性和无法治疗的恶性肿瘤，常见于 AIDS 患者。在这项研究中，我们对 3731 种特征化合物进行了高通量筛选，发现阿糖胞苷是一种有效的 KSHV 诱导的 PEL 抑制剂，该药物已被 FDA 批准用于治疗多种类型的癌症。我们表明，阿糖胞苷通过诱导细胞周期停滞和细胞凋亡，有效地抑制了各种 PEL 细胞的生长。阿糖胞苷抑制宿主 DNA 和 RNA 的合成，从而诱导细胞毒性。此外，阿糖胞苷抑制病毒 DNA 和 RNA 的合成，并诱导 KSHV 主要潜伏蛋白 LANA（潜伏相关核抗原）的快速降解，从而抑制 KSHV 潜伏复制。重要的是，阿糖胞苷有效地抑制了 PEL 细胞中活跃的 KSHV 复制和病毒粒子的产生。最后，阿糖胞苷治疗不仅有效地抑制了 PEL 肿瘤的起始和进展，而且还诱导了异种移植小鼠模型中生长的 PEL 肿瘤的消退。总的来说，我们的研究已经确定阿糖胞苷是治疗 PEL 和消除 KSHV 持续性感染的一种新型治疗药物。原发性渗出性淋巴瘤是一种侵袭性恶性肿瘤，由卡波济肉瘤相关疱疹病毒引起。没有特定的治疗方法，原发性渗出性淋巴瘤的预后很差。通过对特征化合物的高通量筛选，我们发现一种已被 FDA 批准的化合物，阿糖胞苷，是原发性渗出性淋巴瘤的有效抑制剂。我们表明，阿糖胞苷在异种移植小鼠模型中诱导了 PEL 肿瘤的消退。阿糖胞苷抑制宿主和病毒 DNA 和 RNA 的合成，从而诱导细胞毒性。有趣的是，阿糖胞苷诱导 KSHV 主要潜伏蛋白 LANA 的降解，从而抑制 KSHV 潜伏复制，这是 PEL 细胞存活所必需的。此外，阿糖胞苷抑制 KSHV 裂解复制程序，阻止病毒粒子的产生。我们的发现确定阿糖胞苷是治疗 PEL 以及消除 KSHV 持续性感染的一种新型治疗药物。由于阿糖胞苷已被 FDA 批准，它可能是重新用于 PEL 治疗的理想候选药物，并可在进一步的临床试验中进行评估。
