Department of Exper-imental Radiology and Health Physics, Faculty of Medical Science, University of Fukui, Matsuokashimoaizuki, Eiheiji-cho, Yoshida, Fukui 910-1193, Japan.
Int J Mol Med. 2011 Dec;28(6):1033-42. doi: 10.3892/ijmm.2011.760. Epub 2011 Jul 29.
Parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, has a significant thermo-enhancement effect. Modification of thermosensitivity by treatment with PTL prior to hyperthermia was investigated in the human prostate cancer androgen-independent cell lines PC3 and DU145. In addition, we analyzed the mechanisms related to induction of apoptosis or G₂/M cell-cycle arrest via the effects of ERK1/2, p38 and SAPK/JNK signaling on mitogen-activated protein kinase (MAPK). Lethal damage caused by mild hyperthermia at 41.0˚C or 42.0˚C in both cell lines resulted in a low level of thermosensitivity, while sequential combination with PTL showed significant thermosensitization. Step-up hyperthermia (SUH) (42˚C for 30 min, 43.0˚C or 43.5˚C for various periods) reduced the thermosensitivity of the cells to second heating. However, PTL given as pre-treatment prior to SUH prevented SUH-induced thermal tolerance and resulted in significant thermosensitization. Induction of apoptosis by the combination of PTL and hyperthermia at 44.0˚C was determined by the ratio of sub-G1 division cells using flow cytometry, which was increased significantly in comparison with single treatment, and was more effective in PC3 than DU145 cells. The behavior of ERK1/2, p38, and SAPK/JNK signaling in the MAPK cascade by treatment with PTL and hyperthermia were examined by Western blotting. As for PC3 cells, ras-downstream p-ERK1/2 was activated and p-p38 slightly activated by combined treatment with PTL and hyperthermia in comparison with each alone. As for DU145 cells, ERK1/2 was not changed, while p38 and SAPK/JNK were slightly activated by combination treatment. These results were related to increases in the induction of apoptosis, G₂/M cell cycle arrest, and lethal damage of cells via the MAPK cascade. Together, our findings demonstrate that PTL is an effective thermosensitizing agent for multidisciplinary therapy for human prostate cancer.
小白菊内酯（PTL）是一种核因子-κB（NF-κB）抑制剂，具有显著的热增强效应。本研究探讨了小白菊内酯预处理对前列腺癌去势抵抗细胞株 PC3 和 DU145 热敏感性的影响。此外，我们通过分析丝裂原激活蛋白激酶（MAPK）通路中 ERK1/2、p38 和 SAPK/JNK 信号转导对细胞凋亡或 G₂/M 细胞周期阻滞的影响，研究了与诱导细胞凋亡或 G₂/M 细胞周期阻滞相关的机制。在两种细胞系中，41.0°C 或 42.0°C 的温和热疗导致低水平的热敏感性，而与 PTL 的序贯联合则表现出显著的热增敏作用。逐步升温热疗（SUH）（42°C 30 分钟，43.0°C 或 43.5°C 不同时间）降低了细胞对第二次加热的热敏感性。然而，SUH 前给予 PTL 预处理可防止 SUH 诱导的热耐受，并导致显著的热增敏作用。通过流式细胞术检测亚 G1 期细胞分裂的比例，确定了 PTL 与 44.0°C 热疗联合诱导细胞凋亡的情况，与单一治疗相比，该比例显著增加，在 PC3 细胞中比 DU145 细胞更有效。通过 Western blot 检测 PTL 和热疗对 MAPK 级联中 ERK1/2、p38 和 SAPK/JNK 信号的作用。对于 PC3 细胞，与单独处理相比，PTL 和热疗联合处理可激活 ras 下游 p-ERK1/2，轻度激活 p-p38。对于 DU145 细胞，ERK1/2 无变化，而 p38 和 SAPK/JNK 轻度激活。这些结果与通过 MAPK 级联增加细胞凋亡、G₂/M 细胞周期阻滞和细胞致死性损伤有关。总之，我们的研究结果表明，PTL 是一种有效的热增敏剂，可用于人类前列腺癌的多学科治疗。
