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Published on: September 14, 2018
An antibody against DR4 (TRAIL-R1) in combination with doxorubicin selectively kills malignant but not normal
1Department of Microbiology, 173 Ashley Ave, Medical University of South Carolina, Charleston, South Carolina 29403, USA. johnsocv@musc.edu.
Abstract:
Prostate cancer is a major health problem among American men and new treatment approaches are needed. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL/Apo2L) is a death ligand that can induce apoptosis in some but not all cancer cells. Resistance to TRAIL-mediated apoptosis can be overcome by radiation or chemotherapy. The effect of doxorubicin/TRAIL combination therapy was compared among PC3, normal prostate epithelial (PrEC) and stromal (PrSC) cells and cell viability measured by MTS assay. Combination of doxorubicin and TRAIL caused cytotoxicity in all cells tested, although PrSC were more resistant. There was no correlation between TRAIL phenotype and expression of c-FLIP, caspases or TRAIL decoy receptors, although PrSC failed to express DR4. A DR4-specific antibody, which behaved as an agonist in combination with doxorubicin, selectively induced cell death in malignant but not normal prostate cells. Although normal PrEC expressed DR4 as determined by western blot, flow cytometry revealed that only maligant prostate cancer cells (PC3, JCA-1) and not PrEC's exhibited DR4 surface expression. Therefore, combination of doxorubicin and an antibody to DR4 might have therapeutic potential for the treatment of prostate cancer by selectively targeting malignant prostate cells.
Insights
New prostate cancer treatments are needed. Doxorubicin combined with a DR4 antibody selectively targets cancer cells, showing therapeutic potential by inducing cancer cell death while sparing normal cells.
Area of Science:
- Oncology
- Molecular Biology
Background:
- Prostate cancer requires novel therapeutic strategies.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells, but resistance is common.
- Chemotherapy or radiation can overcome TRAIL resistance.
Purpose of the Study:
- To evaluate the efficacy of doxorubicin/TRAIL combination therapy on prostate cancer cells.
- To investigate the role of DR4 expression in TRAIL-mediated apoptosis.
- To explore the potential of a DR4-specific antibody in combination with doxorubicin for prostate cancer treatment.
Main Methods:
- MTS assay was used to measure cell viability of PC3, PrEC, and PrSC cells.
- Western blot and flow cytometry were employed to assess DR4 expression.
- The effects of doxorubicin/TRAIL and doxorubicin/DR4 antibody combinations were analyzed.
Main Results:
- Doxorubicin/TRAIL combination induced cytotoxicity in all tested cells, with PrSC showing higher resistance.
- No correlation was found between TRAIL phenotype and c-FLIP, caspase, or decoy receptor expression.
- A DR4-specific antibody, combined with doxorubicin, selectively killed malignant prostate cancer cells (PC3, JCA-1) but not normal PrEC cells, despite PrEC expressing DR4 intracellularly.
Conclusions:
- Doxorubicin and TRAIL combination therapy shows cytotoxicity but lacks selectivity.
- Malignant prostate cancer cells exhibit surface DR4 expression, unlike normal prostate epithelial cells.
- Combining doxorubicin with a DR4-specific antibody offers a promising, selective therapeutic approach for prostate cancer.
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