Overcoming cisplatin resistance through p53 gene using caffeine in osteosarcoma

在骨肉瘤中使用咖啡因通过 p53 基因克服顺铂耐药性

• 批准号: 11671426
• 负责人: TSUCHIYA Hiroyuki
• 金额: $ 2.3万
• 依托单位: kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671426/
• 关键词: Osteosarcoma; Gsplatin; Drug resistance; p53 gene; Caffeine; 骨肉腫; シスプラチン; p53遺伝子; カフェイン; 薬剤耐性; p53

1) Alteration of p53 gene in human osteosarcoma cell lines : There was no overexpression of p53 gene and no point mutation from exon 5 to exon 8 in both OST cell line (sensitive to cisplatin) and OST-R cell line (resistant to cisplatin). It was considered that these two cell lines expressed wild-type p53 protein.2) Analysis of p53 deletion in cisplatin-resistant human osteosarcoma cell (OST-R) : Deletion of p53 gene was significantly increased in OST-R cells. As the amount of p53 protein was decreased corresponding with this deletion, the function of p53 was suppressed and the instability of chromosome 17 was increased in OST-R.Perhaps, the function loss of p53 gene and protein would be an indicator of acquired cisplatin resistance in human osteosarcoma.3) Alteration of p53 gene expression after chemotherapy and growth inhibition by controlling p53 expression : Caffeine has DNA-repair inhibiting effect and suppress p53 overexpression. The cytocidal effect of cisplatin was increased by caffeine in OST cells, but not in OST-R.The expression of p53 protein was overexpressed after cisplatin treatment and caffeine suppressed this overexpression in OST cells. Caffeine could not overcome the acquired cisplatin-resistance in human osteosarcoma.

1）人骨肉瘤细胞系中p53基因的改变：OST细胞系（对顺铂敏感）和OST-R细胞系（对顺铂耐药）均未出现p53基因过表达，也未出现外显子5至外显子8的点突变。认为这两种细胞系表达野生型p53蛋白。2)顺铂抗性人骨肉瘤细胞(OST-R)中p53缺失分析：OST-R细胞中p53基因缺失显着增加。由于与该缺失相对应的p53蛋白数量减少，OST-R中p53的功能受到抑制，并且17号染色​​体的不稳定性增加。也许，p53基因和蛋白的功能丧失将成为人骨肉瘤中获得性顺铂耐药的一个指标。3）化疗和通过控制p53表达抑制生长后p53基因表达的改变：咖啡因 具有 DNA 修复抑制作用并抑制 p53 过度表达。在OST细胞中，咖啡因增强了顺铂的杀细胞作用，但在OST-R中则没有。顺铂处理后p53蛋白的表达过度表达，咖啡因抑制了OST细胞中的这种过度表达。咖啡因不能克服人骨肉瘤的获得性顺铂耐药性。

项目成果

Tsuchiya H, Mori Y, Ueda Y, Okada G, Tomita K: "Sensitization and Caffeine Potentiation of Cisplatin Cytotoxicity Resulting from Introduction of Wild-Type p53 Gene in Human Osteosarcoma."Anticancer Res. 20. 235-242 (2000)

Tsuchiya H、Mori Y、Ueda Y、Okada G、Tomita K：“在人类骨肉瘤中引入野生型 p53 基因导致顺铂细胞毒性的敏化和咖啡因增强。”抗癌研究。

毛利良彦: "野生型p53遺伝子導入とカフェイン併用によるヒト骨肉腫細胞の抗癌剤感受性の増強"金沢大学十全医学会雑誌. 107. 493-503 (1998)

Yoshihiko Mori：“通过野生型p53基因导入和咖啡因的联合使用增强人骨肉瘤细胞的抗癌药物敏感性”金泽大学十善医学会杂志107. 493-503（1998）。

Asada N, et al: "De Novo Deletions of p53 Gene and Wild-Type p53 Correlate with Acquired Cisplatin-Resistance in Human Osteosarcoma OST Cell Line."Anticancer Res. 19. 5131-5138 (1999)

Asada N 等人：“p53 基因和野生型 p53 的从头删除与人骨肉瘤 OST 细胞系中获得性顺铂耐药性相关。”Anticancer Res。

Tsuchiya H, et al: "Sensitization and Caffeine Potentiation of Cisplatin Cytotoxicity Resulting from Introduction of Wild-Type p53 Gene in Human Osteosarcoma."Anticancer Res. 20. 235-242 (2000)

Tsuchiya H 等人：“在人骨肉瘤中引入野生型 p53 基因导致顺铂细胞毒性的敏化和咖啡因增强”。

Asada N, Tsuchiya H, Tomita K: "De Novo Deletions of p53 Gene and Wild-Type p53 Correlate with Acquired Cisplatin-Resistance in Human Osteosarcoma OST Cell Line."Anticancer Res. 19. 5131-5138 (1999)

Asada N、Tsuchiya H、Tomita K：“p53 基因和野生型 p53 的从头删除与人骨肉瘤 OST 细胞系中获得性顺铂耐药性相关。”抗癌研究。