Cucurbitacin B induces apoptosis of primary effusion lymphoma via disruption of cytoskeletal organization
Cucurbitacin B induces apoptosis of primary effusion lymphoma via disruption of cytoskeletal organization
复制标题
DOI：
10.1016/j.phymed.2021.153545
复制
发表时间：
2021-03-30
期刊：
影响因子：
7.9
通讯作者：
Okada, Seiji
中科院分区：
文献类型：
--
作者：
Ueno, Mikinori;Kariya, Ryusho;Okada, Seiji
背景：原发性渗出性淋巴瘤 (PEL) 是一种侵袭性 B 细胞非霍奇金淋巴瘤，尤其发生在艾滋病患者和感染人类疱疹病毒 8 (HHV-8)/卡波西肉瘤相关疱疹病毒 (KSHV) 的免疫功能低下患者中。尽管采用常规化疗，PEL患者的预后仍较差，需要安全有效的治疗。目的：研究葫芦素B（CuB）对PEL的影响，葫芦素B是葫芦科植物中发现的一种具有多种抗癌活性的三萜化合物。研究设计：我们评估了CuB的体外和体内抗癌活性。方法：通过MTT法测定PEL细胞系的细胞增殖。通过蛋白质印迹分析切割的半胱天冬酶和信号转导相关蛋白。进行Wright染色和Giemsa染色以及免疫荧光染色观察细胞形态。通过流式细胞术分析细胞周期。进行RT-PCR来检测病毒基因表达。采用异种移植小鼠模型评价CuB体内抗癌活性。结果：CuB以剂量依赖性方式（0-50 nM）抑制PEL细胞系（BCBL-1、BC-1、GTO和TY-1）的细胞增殖，并以剂量和时间依赖性方式通过caspase激活诱导BCBL-1细胞凋亡。此外，CuB 通过诱导肌动蛋白聚集和抑制 p-cofilin 水平造成细胞形状破坏，导致 BCBL-1 细胞停滞在 G2/M 期。相比之下，CuB 几乎没有表现出对 p-STAT3 和 p-Akt 激活的抑制，而这些激活是由 KSHV 衍生蛋白组成型激活的。此外，CuB (0.5 mg/kg) 通过腹腔注射显着 (p < 0.05) 抑制异种移植小鼠模型中的实体瘤生长。结论：这项研究表明 CuB 是 PEL 治疗的一种有前景的药物。
Background: Primary effusion lymphoma (PEL) is an aggressive B cell non-Hodgkin lymphoma that develops especially in AIDS patients and immunocompromised patients infected with human herpes virus-8 (HHV-8)/ Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a poor prognosis in patients despite conventional chemotherapeutic treatment, and a safe and efficient therapy is required.Purpose: To examine the effects on PEL of cucurbitacin B (CuB), a triterpene found in plants of the Cucurbitaceae family that has several anti-cancer activities.Study design: We evaluated the anti-cancer activities of CuB in vitro and in vivo.Methods: Cell proliferation of PEL cell lines was measured by MTT assay. Cleaved caspases and signaling transduction associated proteins were analyzed by western blotting. Wright and Giemsa staining and immunofluorescence staining were carried out to observe cell morphology. Cell cycles were analyzed by flow cytometry. RT-PCR was performed to detect viral gene expressions. A xenograft mouse model was employed to evaluate the anti-cancer activity of CuB in vivo.Results: CuB inhibited cell proliferation of PEL cell lines (BCBL-1, BC-1, GTO and TY-1) in a dose-dependent manner (0-50 nM) and induced apoptosis of BCBL-1 cells via caspase activation in a dose- and timedependent manner. In addition, CuB caused cell-shape disruption by inducing actin aggregation and suppressing the p-cofilin level, resulting in BCBL-1 cell arrest at the G2/M phase. In contrast, CuB showed almost no suppression of p-STAT3 and p-Akt activation, which were constitutively activated by KSHV-derived proteins. Furthermore, CuB (0.5 mg/kg) via intraperitoneal injection significantly (p < 0.05) suppressed solid tumor growth in the xenograft mouse model.Conclusion: This study suggests that CuB is a promising agent for PEL treatment.