The sesquiterpene lactone parthenolide is a major component of the feverfew medicinal plant, Tanacetum parthenium. Parthenolide has been extensively studied for its anti-inflammatory and anticancer properties in several tumor models. Parthenolide's antitumor activities depend on several mechanisms but it is mainly known as an inhibitor of the nuclear factor-κB (NF-κB) pathway. This pathway is constitutively activated and induces cell survival in primary effusion lymphoma (PEL), a rare aggressive AIDS-related lymphoproliferative disorder that is commonly caused by the human herpesvirus 8 (HHV-8) infection. The aim of this study is to evaluate the targeted effect of Parthenolide both in vitro and in vivo. Herein, parthenolide significantly inhibited cell growth, induced G₀/G₁ cell cycle arrest, and induced massive apoptosis in PEL cells and ascites. In addition, parthenolide inhibited the NF-ĸB pathway suppressing IĸB phosphorylation and p65 nuclear translocation. It also reduced the expression of the DNA methylase inhibitor (DNMT1). Parthenolide induced HHV-8 lytic gene expression without inhibiting latent viral gene expression. Importantly, DMAPT, the more soluble parthenolide prodrug, promoted delay in ascites development and prolonged the survival of PEL xenograft mice. This study supports the therapeutic use of parthenolide in PEL and encourages its further clinical development.

中文翻译：

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小白菊内酯在原发性渗出性淋巴瘤临床前模型中的抗癌活性

倍半萜内酯小白菊内酯是小白菊药用植物Tanacetum parthenium的主要成分。小白菊内酯因其抗炎和抗癌特性在多种肿瘤模型中得到了广泛研究。Parthenolide 的抗肿瘤活性取决于多种机制，但它主要被称为核因子-κB (NF-κB) 通路的抑制剂。该通路在原发性渗出性淋巴瘤 (PEL) 中被组成性激活并诱导细胞存活，这是一种罕见的侵袭性艾滋病相关淋巴组织增生性疾病，通常由人类疱疹病毒 8 (HHV-8) 感染引起。本研究的目的是评估小白菊内酯在体外和体内的靶向作用。在此，小白菊内酯显着抑制细胞生长，诱导 G ₀ /G₁细胞周期停滞，并在 PEL 细胞和腹水中诱导大量凋亡。此外，小白菊内酯抑制了抑制 IĸB 磷酸化和 p65 核易位的 NF-ĸB 通路。它还降低了 DNA 甲基化酶抑制剂 (DNMT1) 的表达。小白菊内酯在不抑制潜在病毒基因表达的情况下诱导 HHV-8 裂解基因表达。重要的是，DMAPT 是一种更易溶解的小白菊内酯前药，可促进腹水发育延迟并延长 PEL 异种移植小鼠的存活。该研究支持小白菊内酯在 PEL 中的治疗用途，并鼓励其进一步的临床开发。