Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody

Anil Shanker, Alan David Brooks, Carlos Alberto Tristan, John William Wine, Peter John Elliott, Hideo Yagita, Kazuyoshi Takeda, Mark John Smyth, William J Murphy, Thomas Joseph Sayers

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Background: Resistance of tumors to cell death signals poses a complex clinical problem. We explored the therapeutic potential and in vivo toxicity of a combination of bortezomib, a proteasome inhibitor, and MD5-1, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor (DR5) agonist monoclonal antibody, in mouse carcinomas. Methods: Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1 and examined for lung metastases (Renca-FLAG: n = 93; 4T1: n = 40) or monitored for survival (Renca-FLAG: n = 143). Toxicity was assessed by histopathology and hematology. Viability and apoptotic signaling in Renca-FLAG and 4T1 cells treated with bortezomib alone or in combination with TRAIL were analyzed using 3-[4,5-dimethyiazol-2-yl-5]-[3-carboxymethyloxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium assay and by measuring mitochondrial membrane depolarization and caspase-8 and caspase-3 activation. All statistical tests were two-sided. Results: Bortezomib (20 nM) sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis (mean percent decrease in numbers of viable cells, bortezomib + TRAIL vs TRAIL: Renca-FLAG, 95% vs 34%, difference = 61%, 95% confidence interval [CI] = 52% to 69%, P <. 001; 4T1, 85% vs 20%, difference = 65%, 95% CI = 62% to 69%, P <. 001). Sensitization involved activation of caspase-8 and caspase-3 but not mitochondrial membrane depolarization, suggesting an amplified signaling of the extrinsic cell death pathway. Treatment with bortezomib and MD5-1 reduced lung metastases in mice carrying Renca and 4T1 tumors (mean number of metastases, bortezomib + MD5-1 vs MD5-1: Renca-FLAG, 1 vs 8, difference = 7, 95% CI = 5 to 9, P <. 001; 4T1, 1 vs 12, difference = 11, 95% CI = 9 to 12, P <. 001) and increased median survival of mice bearing Renca-FLAG tumors (bortezomib + MD5-1 vs bortezomib + control isotype antibody: 22 of 30 [73%] were still alive at day 180 vs median survival of 42 days [95% CI = 41 to 44 days, P <. 001]) in the absence of obvious toxicity. Conclusion: Bortezomib combined with DR5 agonist monoclonal antibody may be a useful treatment for metastatic solid tumors.

Original languageEnglish (US)
Pages (from-to)649-662
Number of pages14
JournalJournal of the National Cancer Institute
Volume100
Issue number9
DOIs
StatePublished - May 2008
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Shanker, A., Brooks, A. D., Tristan, C. A., Wine, J. W., Elliott, P. J., Yagita, H., Takeda, K., Smyth, M. J., Murphy, W. J., & Sayers, T. J. (2008). Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody. Journal of the National Cancer Institute, 100(9), 649-662. https://doi.org/10.1093/jnci/djn113