Ohtsuka Toshiaki, Buchsbaum Donald, Oliver Patsy, Makhija Sharmila, Kimberly Robert, Zhou Tong
Biomedical Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan.
Oncogene. 2003 Apr 3;22(13):2034-44. doi: 10.1038/sj.onc.1206290.
Using two agonistic monoclonal antibodies specific for each death receptor of TRAIL, 2E12 (anti-human DR4) and TRA-8 (anti-human DR5), we examined the signal transduction of the death receptors in combination with or without chemotherapy agents such as Adriamycin (doxorubicin hydrochloride) and Cisplatin. Our results demonstrated that chemotherapy agents were able to enhance apoptosis-inducing activity of these antibodies against several different types of tumor cell lines through enhanced caspase activation. The combination of the antibodies and chemotherapy agents led to a synergistical activation of the JNK/p38 MAP kinase, which was mediated by MKK4. The combination also caused an increased release of cytochrome c and Smac/DIABLO from mitochondria in parallel with the profound loss of mitochondrial membrane potential. These results suggest that the enhanced activation of the JNK/p38 kinase and the mitochondrial apoptosis pathways play a crucial role in synergistic induction of the death receptor-mediated apoptosis by chemotherapy agents. Thus, the simultaneous targeting of cell surface death receptors with agonistic antibodies and the intracellular JNK/p38 and the mitochondrial death pathways with chemotherapy agents would enhance the efficacy and selectivity of both agents in cancer therapy.
我们使用针对TRAIL的每种死亡受体的两种激动性单克隆抗体，即2E12（抗人DR4）和TR-8（抗人DR5），结合或不结合化疗药物如阿霉素（盐酸多柔比星）和顺铂，研究了死亡受体的信号转导。我们的结果表明，化疗药物能够通过增强半胱天冬酶激活来增强这些抗体对几种不同类型肿瘤细胞系的凋亡诱导活性。抗体与化疗药物的联合导致JNK/p38丝裂原活化蛋白激酶的协同激活，这是由MKK4介导的。联合用药还导致细胞色素c和Smac/DIABLO从线粒体中释放增加，同时线粒体膜电位显著丧失。这些结果表明，JNK/p38激酶的增强激活和线粒体凋亡途径在化疗药物协同诱导死亡受体介导的凋亡中起关键作用。因此，用激动性抗体同时靶向细胞表面死亡受体以及用化疗药物靶向细胞内JNK/p38和线粒体死亡途径，将提高两种药物在癌症治疗中的疗效和选择性。
