Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway.
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.
Ohtsuka
Toshiaki
T
Biomedical Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan.
Buchsbaum
Donald
D
Oliver
Patsy
P
Makhija
Sharmila
S
Kimberly
Robert
R
Zhou
Tong
T
D000111:Acetylcysteine / Q000494:pharmacology; D000230:Adenocarcinoma / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis; D020169:Caspases / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000032:analysis; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000032:analysis; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000276:immunology / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D003574:Cytochrome c Group; C412403:DIABLO protein, human; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin; D000111:Acetylcysteine