Thermosensitization and induction of apoptosis or cell-cycle arrest via the MAPK cascade by parthenolide, an NF-κB inhibitor, in human prostate cancer androgen-independent cell lines

Abstract

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.