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A study on the mechanism of anticancer drug-induced non-apoptotic cell death for a development of new strategy in cancer treatment

研究抗癌药物诱导的非凋亡细胞死亡机制，开发癌症治疗新策略

基本信息

批准号：
17591336
负责人：
KIM Ryungsa
金额：
$ 2.3万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591336/
关键词：
Cancer chemotherapy Cell death Apoptosis Non-apoptosis Autophagy Tumor immunity 抗癌剤胃癌乳癌

项目摘要

In this study, we found the following results :1) Various anticancer drugs induced non-apoptotic cell death such as autophagic cell death in solid malignancies such as gastric and breast cancer ;2) In early phase in response to cell damage, although autophagy was involved in cell survival that produces energy in tumor microenvironment, the autophagy was committed to cell death in late phase when the damage exceeded the threshold ;3) Autophagic cell death was induced by anticancer drugs in apoptosis-resistant cancer cells ;4) Anticancer drugs-induced cell death including apoptosis and autophagic cell death contributed to provoking tumor immunity as a consequence of enforced cell death.The development of molecular targeting drugs such as monoclonal antibody and small molecules is due to the modulation of anticancer drug-induced cell death and provocation of tumor immunity following the cell death. In particular, in the case of monoclonal antibody such as trastuzumab, treatment with trastuzumab provokes tumor immunity which is mediated by not only ADCC but also activation of dendritic cells through Fc γ R. The significance of autophagic cell death in tumor response needs to be demonstrated in clinical practice as a proof of principle, and the assessment will be very important for bridging between preclinical and clinical situation in cancer chemotherapy.

本研究发现：1）在胃癌、乳腺癌等实体肿瘤中，各种抗癌药物均能诱导非凋亡性细胞死亡，如自噬性细胞死亡;2）在细胞损伤的早期，自噬参与了细胞的存活，在肿瘤微环境中产生能量，但在损伤超过阈值的晚期，自噬导致细胞死亡;（3）抗癌药物诱导耐药癌细胞自噬性死亡; 4）抗癌药物-诱导的细胞死亡（包括凋亡和自噬性细胞死亡）有助于激发作为强制性细胞死亡的结果的肿瘤免疫。分子的作用是由于抗癌药物诱导的细胞死亡的调节和细胞死亡后肿瘤免疫的激发。特别是，在单克隆抗体（如曲妥珠单抗）的情况下，曲妥珠单抗治疗可激发肿瘤免疫，这不仅由ADCC介导，还通过Fc γ R激活树突状细胞。自噬性细胞死亡在肿瘤反应中的意义需要在临床实践中作为原理证明来证明，并且评估对于在癌症化疗的临床前和临床情况之间的桥梁将非常重要。