权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A new strategy for the therapy of pancreatic cancer by proton pump inhibitor agents

质子泵抑制剂治疗胰腺癌的新策略

基本信息

批准号：
09671290
负责人：
OHTA Testuo
金额：
$ 2.05万
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：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671290/
关键词：
Bafilomycin A Pancretic cancer Colon cancer Apoptosis Vacuolar type proton pump プロジギオシンプロトンポンプインヒビターバフィロマイシン Proton pump inhibitor Bafilomycin A1 消化器癌

项目摘要

The effect of bafilomycin A1 on tumor growth in vitro and in vivo was examined using an MTT assay and an in vivo tumor model. Five pancretic cancer cell lines seven colon cancer cell lines were used in this study. The ID 5 0 of bafilomycin A1 by the MTT assay was from 5 nM to 40 nM in every cell lines. Phosphatidylserine externalization of cancer cells was found 24 hr after bafilomycin A1 treatment. In DNA analysis, a ladder of fragmented DNA was detected 48 hr after bafilomycin A1 treatment. Morphologically, cancer cells showed cytoplasmic blebbing and a decreased number of microvilli 24 hr after the treatment, and the characteristic morphological changes of apoptosis, including nuclear chromatin condensation and fragmentation, loss of microvilli and cell shrinkage, were observed 48 hr after the treatment. Caspase 3 and caspase 9 proteins were activated 48 hr after treatment, however, caspase 6 and caspase 7 proteins were not activated during the treatment by Western blotting, suggesting a mitochondria-dependent apoptotic pathway. These apoptotic changes were not inhibited by 10 mM imidazole treatment. Next, nude mice bearing a xenografted Capan-1 cell line tumor received 4 weeks of bafilomycin A1 (1.0 mg/kg/day). This treatment significantly inhibited tumor growth compared with controls after 21 days. 25C-prodigiosin also showed the same inhibitory effect on a xenografted Capan-1 cell line tumor. Histopathological examination of tumor cells in the treatment group demonstrated signs of apoptosis with chromatin condensation and cell shrinkage. These observations suggest that bafilomycin A1 inhibits the growth of human colon and pancreatic cancer cells through apoptosis.

采用MTT法和体内肿瘤模型研究巴霉素A1对体外和体内肿瘤生长的影响。采用5株胰腺癌细胞株和7株结肠癌细胞株进行研究。MTT法测定巴菲霉素A1在各细胞系中的id50在5 ~ 40 nM范围内。在巴菲霉素A1治疗24小时后发现癌细胞有磷脂酰丝氨酸外化。在DNA分析中，在巴非霉素A1治疗48小时后检测到DNA片段的阶梯。形态学上，肿瘤细胞在给药24小时后出现细胞质起泡，微绒毛减少；在给药48小时后，肿瘤细胞出现核染色质凝集、断裂、微绒毛缺失、细胞收缩等特征性凋亡形态学变化。Caspase 3和Caspase 9蛋白在处理48小时后被激活，而Caspase 6和Caspase 7蛋白在处理期间未被激活，提示凋亡途径依赖于线粒体。10 mM咪唑未抑制细胞凋亡的变化。接下来，移植了Capan-1细胞系肿瘤的裸鼠接受4周的巴菲霉素A1 （1.0 mg/kg/天）治疗。21天后，与对照组相比，该治疗显著抑制肿瘤生长。25C-prodigiosin对异种移植的Capan-1细胞系肿瘤也有相同的抑制作用。治疗组肿瘤细胞病理检查显示细胞凋亡，染色质凝集，细胞收缩。这些观察结果表明，巴非霉素A1通过凋亡抑制人结肠癌和胰腺癌细胞的生长。