Augmentation of Transport for Cisplatin-glutathione Adduct in Cisplatinresistant Cancer Cells

增强顺铂-谷胱甘肽加合物在顺铂耐药癌细胞中的转运

• 批准号: 06670145
• 负责人: KONDO Takahito
• 金额: $ 1.41万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670145/
• 关键词: Glutathione; gamma-Glutamylcystein Synthetase; Citotoxicity; Drag Resistance; Antioxidant; Transport; 酸化的ストレス

We studied the outward transport of cisplatin (CDDP) -glutathione (GSH) adduct (DDP-GSH) in CDDP-resistant cancer cells. Incubating the cells in the presence of CDDP resulted in the formation of an adduct with GSH and subsequent transport outside the cells. We used human colonic cancer cells sensitive (HCT8) and resistant (HCT8DDP) to CDDP,and human ovarian cancer cells sensitive (A2780) and resistant (A2780DDP) to CDDP as materials.The concentration of intracellular GSH was higher in the resistant cells (118.7<plus-minus>5.9nmol/10^6 HCT8DDP vs 19.0<plus-minus>1.0nmol/10^6 HCT8 and 24.1<plus-minus>1.2nmol/10^6 A2780DDP vs 9.4<plus-minus>0.5nmol/10^6 A2780, respectively). The activity of the GSH synthesizing enzyme, gamma-glutamylcysteine synthetase (gamma-GCS) was higher in the CDDP-resistant cells (7.1<plus-minus>0.2milliunits/10^6 HCT8DDP vs 2.2<plus-minus>0.1milliunits/10^6 HCT8, and 2.9<plus-minus>0.1milliunits/10^6 A2780DDP vs 1.4<plus-minus>0.1milliunits/10^6 A2780 respectively) … More . Furthermore, immunological levels of gamma-GCS and the expression of gamma-GCS mRNA were higher in these CDDP-resistant cells than those in the control cells in accordance with the change in the concentration of GSH.DDP-GSH transport increased in the CDDP-resistant colonic cancer cells by 219% (324<plus-minus>12fmol/10^6 HCT8DDP cells/min vs 148<plus-minus>11fmol/10^6 HCT8 cells/min) and the CDDP-resistant ovarian cancer cells by 126% (127<plus-minus>7fmol/10^6 A2780DDP cells/min vs 101<plus-minus>8fmol/10^6 A2780 cells/min).DDP-GSH transport was also estimated using inside-out vesicles from these cells. The active transport of DDP-GSH was 243% of HCT8 in HCT8DDP and 121% of A2780 in A2780DDP.These data suggest that the acquisition of CDDP-resistance in cancer cells is due partly to the increase in the transport of DDP-GSH outside the cells as well as the increase in the concentration of GSH.Immunological estimation of the membrane proteins against human erythrocyte glutathione Sconjugate-stimulated Mg^<2+>-ATPase sera resulted in no apparent cross reactivity, suggesting that there are several transport systems for DDP-GSH. Less

我们研究了顺铂（CDDP）-谷胱甘肽（GSH）加合物（DDP-GSH）在顺铂耐药癌细胞中的向外转运。在CDDP存在下孵育细胞导致与GSH形成加合物并随后运输到细胞外。以顺铂敏感的人结肠癌细胞（HCT 8）和耐药的人结肠癌细胞（HCT 8DDP）以及对顺铂敏感的人卵巢癌细胞（A2780）和对顺铂耐药的人卵巢癌细胞（A2780 DDP）为材料，发现耐药细胞内GSH浓度较高（分别为118.7 <plus-minus>± 5.9nmol/10^6 HCT 8DDP vs 19.0 ± <plus-minus>1.0nmol/10^6 HCT 8和24.1 ± <plus-minus>1.2nmol/10^6 A2780 DDP vs 9.4 <plus-minus>± 0.5nmol/10^6 A2780）。GSH合成酶γ-谷氨酰半胱氨酸合成酶（γ-GCS）活性在CDDP抗性细胞中较高（分别为7.1 <plus-minus>± 0.2毫单位/10^6 HCT 8 DDP vs 2.2 ± <plus-minus>0.1毫单位/10^6 HCT 8，2.9 <plus-minus>± 0.1毫单位/10^6 A2780 DDP vs 1.4 <plus-minus>± 0.1毫单位/10^6 A2780）。 ...更多信息 . CDDP耐药结肠癌细胞和卵巢癌细胞的DDP-GSH转运分别增加了219%（324 <plus-minus>12 fmol/10^6 HCT 8 DDP cells/min vs 148 <plus-minus>11 fmol/10^6 HCT 8 cells/min）和126%（127 <plus-minus>7 fmol/10^6 A2780 DDP cells/min vs 101 <plus-minus>8 fmol/10^6 A2780 cells/min）。HCT 8DDP对DDP-GSH的主动转运是HCT 8的243%，A2780 DDP对A2780的121%。这些数据表明，癌细胞获得CDDP抗性的部分原因是由于DDP-GSH向细胞外转运的增加以及GSH浓度的增加。2+&gt;-ATP酶血清无明显交叉反应，提示DDP-GSH有多种转运系统。少

项目成果

Shinji Goto: "Augmentation of Transport for Cisplatin-glutathione Adduct in cisplatin-resistant Cancer Cells^1" Cancer Research. 55. 4297-4301 (1995)

Shinji Goto：“增强顺铂-谷胱甘肽加合物在顺铂耐药癌细胞^1中的运输”癌症研究。

Shinji Coto et.al.: "Augmentation of Transport for Cisplatin-glutathione Adduct in Cisplatin-resistant Cancer Cells" Cancer Research. 55. 4297-4301 (1995)

Shinji Coto 等人：“增强顺铂-谷胱甘肽加合物在顺铂耐药癌细胞中的运输”癌症研究。

Shinji Goto: "Augmentation of Transport for Cisplatin-glutathione Adduct in Cisplatin-resistant Cancer Cells" Cancer Research. 55. 4297-4301 (1995)

Shinji Goto：“增强顺铂-谷胱甘肽加合物在顺铂耐药癌细胞中的运输”癌症研究。