Fundamental study on molecular chaperone cancer therapy

分子伴侣癌症治疗的基础研究

• 批准号: 12670899
• 负责人: OHNISHI Ken
• 金额: $ 0.7万
• 依托单位: Nara Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670899/
• 关键词: molecular chaperone; glycerol; radiation; hypothermia; anti-cancer agent; apoptosis; gene transfection; p53; グリセロール

The aim of this study is to develop new cancer therapy, which is based on a chemical chaperone (glycerol) to change conformation of mutant p53 (mp53) protein to wild-type p53 (wtp53) protein and restore the function of wtp53. Transfection with wtp53 to p53-null cells increased the thermo sensitivity and enhanced heat-induced apoptosis.Human annalistic thyroid carcinoma cells (8305c) transected with temperature sensitive mp53 showed radio-, heat- or CDDP-sensitivity under culture condition inducing wtp53. Human aqueous cell carcinoma (SAS/mp53) cells transected with mp53 were resistant to X-ray or CDDP compared with the control cells having normal function of p53 (SAS/neo). However, SAS/mp53 cells became sensitive to X-ray or CDDP after X-ray or CDDP treatment in the presence of glycerol, while that of SAS/neo cells did not. X-ray or CDDP-induced apoptosis was suppressed in SAS/mp53 cells, whereas X-ray or CDDP treatment combined with glycerol induced efficient DNA fragmentation and apoptotic bodies in SAS/mp53 cells. Growth delay was observed in SAS/mp53 tumors transplanted in nude mice when they were treated with CDDP in the presence of glycerol. From these results, radiation and chemical therapies combined chemical chaperone therapy might improve the outcome of cancer therapies.

本研究的目的是开发一种新的癌症治疗方法，该方法基于化学伴侣（甘油）来改变突变型p53（mp53）蛋白的构象为野生型p53（wtp 53）蛋白，并恢复wtp 53的功能。转染p53基因的人甲状腺癌细胞（8305 c）在诱导wtp 53表达的培养条件下，表现出对辐射、热或CDDP的敏感性。与p53功能正常的对照细胞（SAS/neo）相比，用mp53横切的人眼水细胞癌（SAS/mp53）细胞对X射线或CDDP有抵抗作用。而SAS/neo细胞对X射线或CDDP不敏感，而SAS/mp53细胞对X射线或CDDP敏感。X射线或CDDP诱导的SAS/mp53细胞凋亡被抑制，而X射线或CDDP处理结合甘油诱导有效的DNA片段化和凋亡小体在SAS/mp53细胞。当在甘油存在下用CDDP处理时，在裸鼠中移植的SAS/mp53肿瘤中观察到生长延迟。从这些结果来看，放射和化学疗法结合化学伴侣疗法可能会改善癌症治疗的结果。

项目成果

Matsumoto,H., et al.: "Interactive effects of nitric oxide and p53 on cellular thermosensitivity."Jpn.J.Hyperthermic Oncol.. 16. 69-82 (2000)

Matsumoto,H., et al.：“一氧化氮和 p53 对细胞热敏感性的相互作用。”Jpn.J.Hyperthermic Oncol.. 16. 69-82 (2000)

Takahashi, A., et al.: "WAF1 accumulation by carbon-ion beams and α-particle irradiation in human glioblastoma cultured cells"Int.J.Radiat.Biol.. 76. 335-341 (2000)

Takahashi, A., et al.：“人胶质母细胞瘤培养细胞中碳离子束和 α 粒子照射的 WAF1 积累” Int.J.Radiat.Biol.. 76. 335-341 (2000)

Takahashi, A., et al.: "Radiation response of apoptosis in C57BL/6N mouse spleen after whole-body irradiation"Int. J. Radiat. Biol.. 77. 939-946 (2001)

Takahashi, A. 等人：“全身照射后 C57BL/6N 小鼠脾脏细胞凋亡的放射反应”Int。

Takahashi, A., et al.: "Radiation-induced apoptosis in scid mouse spleen after low dose-rate irradiation"Int.J.Radiat.Biol.. (in press). (2002)

Takahashi, A. 等人：“低剂量率照射后 scid 小鼠脾脏中辐射诱导的细胞凋亡”Int.J.Radiat.Biol..（出版中）。

Ohnishi, K., T.Ohnishi: "Heat-induced p53-dependent signal transduction and its role in hyperthermic cancer therapy"Int.J.Hyperthermia. 17. 415-427 (2001)

Ohnishi, K., T.Ohnishi：“热诱导的 p53 依赖性信号转导及其在癌症高温治疗中的作用”Int.J.Hyperthermia。