Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand
Anil Shanker1, Alan David Brooks, Carlos Alberto Tristan
1Laboratory of Experimental Immunology, Cancer and Inflammation Program, SAIC-Frederick, Inc, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
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.
Insights
Bortezomib combined with a DR5 agonist monoclonal antibody effectively reduced lung metastases and improved survival in mouse models. This combination therapy shows promise for treating metastatic solid tumors without significant toxicity.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Tumor resistance to apoptosis signals presents a significant clinical challenge.
- Investigating therapeutic strategies to overcome this resistance is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To evaluate the therapeutic efficacy and in vivo toxicity of combining bortezomib (a proteasome inhibitor) with MD5-1 (a DR5 agonist monoclonal antibody).
- To assess the combination's impact on lung metastases and overall survival in mouse carcinoma models.
Main Methods:
- Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1.
- Lung metastases and survival were monitored; toxicity was assessed via histopathology and hematology.
- In vitro studies analyzed cell viability, apoptosis signaling, and caspase activation.
Main Results:
- Bortezomib sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis by activating caspase-8 and caspase-3.
- The combination of bortezomib and MD5-1 significantly reduced lung metastases in both tumor models.
- Median survival was increased in mice bearing Renca-FLAG tumors treated with the combination therapy, with no obvious toxicity.
Conclusions:
- Bortezomib in combination with a DR5 agonist monoclonal antibody demonstrates therapeutic potential.
- This combination may serve as a valuable treatment strategy for metastatic solid tumors.
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