Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway

Toshiaki Ohtsuka, Donald Buchsbaum, Patsy Oliver, Sharmila Makhija, Robert Kimberly, Tong Zhou

Research output: Contribution to journalArticle

133 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)2034-2044
Number of pages11
JournalOncogene
Volume22
Issue number13
DOIs
Publication statusPublished - Apr 3 2003
Externally publishedYes

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Keywords

  • Apoptosis
  • Chemotherapy
  • JNK
  • Mitochondria
  • TRAIL receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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