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Search for cell-death inducing antitumor agents based on the anti-tumor activity of V-ATPase inhibitors

基于V-ATP酶抑制剂的抗肿瘤活性寻找细胞死亡诱导抗肿瘤药物

基本信息

批准号：
10557221
负责人：
OHKUMA Shoji
金额：
$ 8.32万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

In this project, we have investigated the mechanism of incuction of neurite outgrowth (NOG), cell differentiation, growth inhibiton and apoptosis by inhibitors against V-ATPases, such as bafilomycin, concanamycins and prodigiosins, and the mechanism of proton transport in V-ATPases.We found that (1) V-ATPase inhibitors like bafilomycin induced apoptosis and NOG in new RNA-, protein-syntheses, and serine/threonine kinase-dependent mannaer, and K-252a- or A-kinase-independent manner, but they are different from each other : apoptosis-induction is different from NOG-induction in its insensitivitiy in tyrosin-phosphatase, arachidonate-cascade or Calmodulin-kinase independent manner, (2) apoptosis and NOG are also induced by prodigiosins but they are not induced by its H^+/Cl^- symporting activities, and (3) apoptosis or NOG is not induced by pH-differences between inside and outside of cells, because they are not induced by NH_4Cl, (4) We have succeeded in the synsesis of concanamycin A-photoaffinity probes active in V-ATPase-inhibition. (5) Prodigiosins are H^+/Cl^- symporters that uncoupled ATPases like F-, V-, P-ATPase and electron transport activity, in which prodigiosins inhibited proton-transport but no ATP hydrolysis (or electron transport) activiteis. Prodigiosins also strongly and reversibly uncoupled (H^+/K^+) ATPase-dependent proton-translocation from hog gastric mucosa. (6) We have succeeded in the cloning, proton-pump dependent ATP synthesis, and determation of operon structure of V-ATPase from a eubacterium (Thermus termophilus).

在本项目中，我们研究了V-ATP酶抑制剂（如巴弗洛霉素、刀刀霉素和灵菌红素）诱导神经突生长（NOG）、细胞分化、生长抑制和凋亡的机制，以及V-ATP酶中质子转运的机制。我们发现（1）V-ATP酶抑制剂（如巴弗洛霉素）可诱导细胞凋亡和细胞凋亡。 NOG以新的RNA、蛋白质合成和丝氨酸/苏氨酸激酶依赖性方式，以及K-252a或A激酶独立方式，但它们彼此不同：凋亡诱导不同于NOG诱导，其不敏感性以酪氨酸磷酸酶、花生四烯酸级联或钙调蛋白激酶独立方式，(2) 细胞凋亡和NOG也由灵菌红素诱导，但它们不是由其H^+/Cl^-同向活性诱导的，并且（3）细胞凋亡或NOG不是由细胞内外pH差异诱导的，因为它们不是由NH_4Cl诱导的，（4）我们已经成功合成了具有V-ATP酶抑制活性的刀那霉素A-光亲和探针。 (5)灵菌红素是H^+/Cl^-同向转运蛋白，可解偶联F-、V-、P-ATP酶等ATP酶和电子传递活性，其中灵菌红素抑制质子传递但不抑制ATP水解(或电子传递)活性。灵菌红素还能强烈且可逆地解偶联（H^+/K^+）来自猪胃粘膜的ATP酶依赖性质子易位。 (6) 我们成功地从真细菌(Thermus termophilus)中克隆、质子泵依赖性ATP合成以及操纵子结构的确定。