Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens-University, Graz, Austria.
Planta Med. 2012 Nov;78(16):1749-56. doi: 10.1055/s-0032-1315385. Epub 2012 Oct 9.
Human soft tissue sarcomas represent a rare group of malignant tumours that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment. In this study, we investigated the effects of costunolide and dehydrocostus lactone, which have been isolated from Saussurea lappa using activity-guided isolation, on three soft tissue sarcoma cell lines of various origins. The effects on cell proliferation, cell cycle distribution, apoptosis induction, and ABC transporter expression were analysed. Both compounds inhibited cell viability dose- and time-dependently. IC50 values ranged from 6.2 µg/mL to 9.8 µg/mL. Cells treated with costunolide showed no changes in cell cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 h. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction. In addition, the influence of costunolide and dehydrocostus lactone on the expression of ATP binding cassette transporters related to multidrug resistance (ABCB1/MDR1, ABCC1/MRP1, and ABCG2/BCRP1) was examined using real-time RT-PCR. The expressions of ABCB1/MDR1 and ABCG2/BCRP1 in liposarcoma and synovial sarcoma cells were significantly downregulated by dehydrocostus lactone. Our data demonstrate for the first time that dehydrocostus lactone affects cell viability, cell cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumours.
人软组织肉瘤代表了一组罕见的恶性肿瘤，这些肿瘤在治疗失败后常常表现出化疗耐药性和增加的转移潜能。在这项研究中，我们使用活性导向分离法从独活中分离出的木香烃内酯和去氢木香内酯，研究了它们对三种不同来源的软组织肉瘤细胞系的影响。分析了它们对细胞增殖、细胞周期分布、细胞凋亡诱导和 ABC 转运蛋白表达的影响。这两种化合物均能剂量和时间依赖性地抑制细胞活力。IC50 值范围为 6.2 µg/mL 至 9.8 µg/mL。用木香烃内酯处理的细胞在细胞周期中没有变化， caspase 3/7 活性变化不大，在 24 和 48 h 后 cleaved caspase-3 水平较低。去氢木香内酯导致 G1 期细胞显著减少，S 和 G2/M 期细胞增加。此外，它还导致 caspase 3/7 活性增强、cleaved caspase-3 和 cleaved PARP 增加，表明诱导细胞凋亡。此外，还使用实时 RT-PCR 研究了木香烃内酯和去氢木香内酯对与多药耐药相关的 ATP 结合盒转运蛋白（ABCB1/MDR1、ABCC1/MRP1 和 ABCG2/BCRP1）表达的影响。去氢木香内酯显著下调脂肪肉瘤和滑膜肉瘤细胞中 ABCB1/MDR1 和 ABCG2/BCRP1 的表达。我们的数据首次表明，去氢木香内酯影响软组织肉瘤细胞系的细胞活力、细胞周期分布和 ABC 转运蛋白表达。此外，它还导致 caspase 3/7 活性以及 caspase-3 和 PARP 的裂解，这是细胞凋亡的指标。因此，该化合物可能是开发针对耐药肿瘤的治疗药物的有前途的先导候选物。
