Chang Yu-Hsun, Wu Kun-Chi, Ding Dah-Ching
Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Foundation, and Tzu Chi University, Hualien, Taiwan.
Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Foundation, and Tzu Chi University, Hualien, Taiwan.
J Cancer. 2021 Mar 30;12(11):3126-3135. doi: 10.7150/jca.51650. eCollection 2021.
High-grade serous ovarian cancer (HGSOC) constitutes 80% of ovarian cancer. Cancer stem cells (CSCs) are responsible for most of the tumor metastasis and chemoresistance. n-Butylidenephthalide (BP) is a potential anti-tumor agent for treating a variety of cancers. The aim of this study was to evaluate the effect of BP on CSCs of HGSOC. CSCs were isolated using the CSC marker (ALDH; aldehyde dehydrogenase) from KURAMOCHI and OVSAHO cells (HGSOC cell lines). The cell proliferation, IC50 (the half-maximal inhibitory concentration), cell migration and invasion, TUNEL (terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling) assay, western blot of ovarian CSC were evaluated. The animal xenograft studies were evaluated on an immunodeficient mouse model. The results showed the proliferation of ALDH+ cells was greater than that of ALDH- cells. The dosage of IC50 of BP was higher in ALDH+ cells than in mixed cancer cells (317.2 vs. 206.5 μg/ml) in KURAMOCHI cells, but not in OVSAHO cells (61.1 vs. 48.5 μg/ml). BP could inhibit the migration and invasion of both cancer stem cells. BP treatment could activate apoptosis signaling, as indicated by the TUNEL assay and the increased expression of cleaved caspase-3, -7, and -9 but not cleaved caspase-8. A low dose of BP (20 and 25 μg/mL) treatment could increase the toxicity of taxol and cisplatin. In the animal model, BP (200 mg/kg) treatment also decreased the KURAMOCHI and OVSAHO tumor growth rate and induced tumor apoptosis. In conclusion, BP could kill ALDH+ CSCs of HGSOC and by inducing apoptosis. BP may provide a new therapeutic approach for HGSOC.
高级别浆液性卵巢癌（HGSOC）占卵巢癌的80%。癌症干细胞（CSCs）是肿瘤转移和化疗耐药的主要原因。正丁烯基苯酞（BP）是一种治疗多种癌症的潜在抗肿瘤药物。本研究旨在评估BP对HGSOC癌症干细胞的作用。使用CSC标志物（醛脱氢酶，ALDH）从KURAMOCHI和OVSAHO细胞（HGSOC细胞系）中分离出癌症干细胞。评估细胞增殖、IC50（半数最大抑制浓度）、细胞迁移和侵袭、TUNEL（末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记）检测以及卵巢癌干细胞的蛋白质免疫印迹。在免疫缺陷小鼠模型上评估动物异种移植研究。结果显示，ALDH+细胞的增殖大于ALDH-细胞。在KURAMOCHI细胞中，BP对ALDH+细胞的IC50剂量高于混合癌细胞（317.2对206.5μg/ml），但在OVSAHO细胞中并非如此（61.1对48.5μg/ml）。BP可抑制两种癌症干细胞的迁移和侵袭。BP处理可激活凋亡信号，TUNEL检测以及裂解的caspase-3、-7和-9表达增加表明了这一点，但裂解的caspase-8未增加。低剂量BP（20和25μg/mL）处理可增加紫杉醇和顺铂的毒性。在动物模型中，BP（200mg/kg）处理也降低了KURAMOCHI和OVSAHO肿瘤的生长速率并诱导肿瘤凋亡。总之，BP可通过诱导凋亡杀死HGSOC的ALDH+癌症干细胞。BP可能为HGSOC提供一种新的治疗方法。
