Abstract
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 Q1chemotherapy 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.
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Acknowledgements
We thank Dr WJ Koopman (University of Alabama at Birmingham, Birmingham, AL, USA) for helpful discussion; Drs R Jope (University of Alabama at Birmingham, Birmingham, AL, USA) and CG Taylor (University of Louisville, Louisville, KY, USA) for providing 1321N1, and UL-3B and UL-3C cells, respectively. This work was supported in part by Sankyo Co., Ltd of Japan, and by the Juvenile Diabetes Foundation, the Arthritis Foundation, the Cystic Fibrosis Foundation, and the NIH Grants AR44982, CA89019 and CA83591 (to TZ).
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Ohtsuka, T., Buchsbaum, D., Oliver, P. et al. Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway. Oncogene 22, 2034–2044 (2003). https://doi.org/10.1038/sj.onc.1206290
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DOI: https://doi.org/10.1038/sj.onc.1206290
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