Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma
Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma
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DOI：
10.1172/jci64503
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发表时间：
2013-06-01
影响因子：
15.9
通讯作者：
Ramos, Juan Carlos
中科院分区：
文献类型：
--
作者：
Bhatt, Shrub;Ashlock, Brittany M.;Ramos, Juan Carlos
原发性渗出性淋巴瘤(PEL)是一种罕见的侵袭性B细胞淋巴瘤，由卡波西肉瘤相关疱疹病毒(KSHV)引起。目前的化疗方法结果令人沮丧，迫切需要新的PEL疗法。此前，我们在荷瘤免疫受损小鼠的直接异种移植模型中建立了蛋白酶体抑制剂Bortezomib(BTZ)的治疗，与阿霉素治疗后相比，BTZ治疗提高了存活率。在这里，我们证明了BTZ与组蛋白去乙酰化酶(HDAC)抑制剂Suberoylanilide草酮酸(SAHA，也称为voinostat)联合使用可以有效地重新激活KSHV的裂解复制并诱导PEL细胞死亡，从而显著延长携带PEL的小鼠的存活时间。重要的是，BTZ阻断了KSHV晚期裂解基因的表达，最终抑制了体内完整的裂解级联反应和感染性病毒的产生。BTZ处理导致半胱氨酸天冬氨酸氨基转移酶激活并诱导DNA损伤，表现为磷酸化的γ-H_(AX)和p53的积累。在BTZ治疗中加入SAHA是协同作用的，因为SAHA诱导了p53的早期乙酰化，并减少了与其负调控因子MDM2的相互作用，从而增强了BTZ的作用。在没有增加病毒血症的情况下，KSHV感染的小鼠的PEL细胞被根除，这为在PEL中使用蛋白酶体/HDAC抑制剂联合治疗提供了强有力的理由。
Primary effusion lymphoma (PEL) is a rare form of aggressive B cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Current chemotherapy approaches result in dismal outcomes, and there is an urgent need for new PEL therapies. Previously, we established, in a direct xenograft model of PEL-bearing immune-compromised mice, that treatment with the proteasome inhibitor, bortezomib (Btz), increased survival relative to that after treatment with doxorubicin. Herein, we demonstrate that the combination of Btz with the histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA, also known as vorinostat) potently reactivates KSHV lytic replication and induces PEL cell death, resulting in significantly prolonged survival of PEL-bearing mice. Importantly, Btz blocked KSHV late lytic gene expression, terminally inhibiting the full lyric cascade and production of infectious virus in vivo. Btz treatment led to caspase activation and induced DNA damage, as evidenced by the accumulation of phosphorylated gamma H2AX and p53. The addition of SAHA to Btz treatment was synergistic, as SAHA induced early acetylation of p53 and reduced interaction with its negative regulator MDM2, augmenting the effects of Btz. The eradication of KSHV-infected PEL cells without increased viremia in mice provides a strong rationale for using the proteasome/HDAC inhibitor combination therapy in PEL.