title: 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.
authors.affiliation: Department of Exper-imental Radiology and Health Physics, Faculty of Medical Science, University of Fukui, Matsuokashimoaizuki, Eiheiji-cho, Yoshida, Fukui 910-1193, Japan. hayashis@u-fukui.ac.jp
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hayashi
authors.forename: Ken
authors.initials: K
authors.lastname: Koshiba
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatashita
authors.forename: Takefumi
authors.initials: T
authors.lastname: Sato
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Jujo
authors.forename: Ryuta
authors.initials: R
authors.lastname: Suzuki
authors.forename: Yukie
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shioura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases