Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea.
Department of Anatomy, College of Medicine, Kosin University, Busan, 49267, Republic of Korea.
Cancer Lett. 2019 Feb 28;443:25-33. doi: 10.1016/j.canlet.2018.11.027. Epub 2018 Nov 29.
Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which remains incurable. Plant extracts are a potential source of potent anticancer medicines. In this study, we investigated the effect of isolinderalactone from Lindera aggregata on tumor growth using U-87 human glioblastoma cells. Treatment with isolinderalactone inhibited cell viability and promoted apoptotic cell death. In addition, intraperitoneal injection of isolinderalactone significantly inhibited tumor growth in a human GBM xenograft mouse model. To identify the proteins involved in the induction of apoptosis in isolinderalactone-treated cells, we performed a human apoptosis proteome array analysis and western blotting. Isolinderalactone suppressed the expression of B-cell lymphoma 2 (BCL-2), as well as of survivin and X-linked inhibitor of apoptosis protein (XIAP), known as apoptosis inhibitors, and increased the level of cleaved caspase-3. In addition, isolinderalactone treatment increased cleaved poly(ADP-ribose) polymerase (PARP) and DNA damage. In xenograft tumor tissues, we observed high immunofluorescence of cleaved caspase-3 and TUNEL in isolinderalactone-treated group. Taken together, isolinderalactone enhances U-87 GBM cell apoptosis in vitro and in vivo and retards tumor growth, suggesting that isolinderalactone may be a potential candidate for anti-glioblastoma drug development.
多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，目前仍然无法治愈。植物提取物是潜在的强效抗癌药物来源。在这项研究中，我们使用 U-87 人胶质母细胞瘤细胞研究了来自山胡椒的异连翘脂素对肿瘤生长的影响。异连翘脂素处理抑制了细胞活力并促进了细胞凋亡。此外，异连翘脂素腹腔注射显著抑制了人 GBM 异种移植小鼠模型中的肿瘤生长。为了鉴定异连翘脂素处理细胞中诱导细胞凋亡涉及的蛋白质，我们进行了人类细胞凋亡蛋白质组阵列分析和 Western blot。异连翘脂素抑制了 B 细胞淋巴瘤 2（BCL-2）、存活素和 X 连锁凋亡抑制蛋白（XIAP）的表达，这些蛋白是已知的凋亡抑制剂，并增加了裂解的半胱天冬酶-3 的水平。此外，异连翘脂素处理增加了裂解的多聚（ADP-核糖）聚合酶（PARP）和 DNA 损伤。在异种移植肿瘤组织中，我们观察到异连翘脂素处理组中 cleaved caspase-3 和 TUNEL 的免疫荧光强度较高。总之，异连翘脂素增强了 U-87 GBM 细胞在体外和体内的凋亡，并减缓了肿瘤生长，表明异连翘脂素可能是开发抗胶质母细胞瘤药物的潜在候选物。
