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

在本研究中，我们发现：1)各种抗癌药物诱导的非凋亡性细胞死亡，如胃癌、乳腺癌等实体恶性肿瘤的自噬细胞死亡；2)在细胞损伤的早期阶段，虽然自噬参与了肿瘤微环境中产生能量的细胞存活，但当损伤超过阈值时，自噬致力于细胞死亡；3)抗癌药物在抗凋亡癌细胞中诱导自噬细胞死亡；4)抗癌药物诱导的细胞死亡，包括细胞凋亡和自噬细胞死亡，是细胞被强迫死亡后激发肿瘤免疫的结果。分子靶向药物如单抗和小分子药物的发展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。特别是在单抗如曲妥珠单抗的情况下，曲妥珠单抗可激发肿瘤免疫，这种免疫不仅由adcc介导，还通过FcγR激活树突状细胞。自噬细胞死亡在肿瘤反应中的重要性需要在临床实践中作为原理的证明来证明，评估将是癌症化疗中临床前和临床之间的桥梁非常重要。

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.