AI Article Synopsis
- Pseudomonas exotoxin (PE)-based immunotoxins are effective in treating hairy cell leukemia, but show limited success in other cancers like colon cancer.
- In a study using the colon cancer cell line DLD1, researchers found that these immunotoxins did not induce cell death despite halting protein production, leading to further investigation into their resistance mechanisms.
- The combination of the immunotoxin and the drug ABT-737 significantly activated a key cell death pathway, showcasing that ABT-737 enhances the effectiveness of PE-related immunotoxins, particularly due to its impact on endoplasmic reticulum stress responses.
Article Abstract
Pseudomonas exotoxin (PE)-based immunotoxins (antibody-toxin fusion proteins) have achieved frequent complete remissions in patients with hairy cell leukemia but far fewer objective responses in other cancers. To address possible mechanisms of resistance, we investigated immunotoxin activity in a model system using the colon cancer cell line, DLD1. Despite causing complete inhibition of protein synthesis, there was no evidence that an immunotoxin targeted to the transferrin receptor caused apoptosis in these cells. To address a possible protective role of prosurvival Bcl-2 proteins, the BH3-only mimetic, ABT-737, was tested alone or in combination with immunotoxins. Neither the immunotoxin nor ABT-737 alone activated caspase 3, whereas the combination exhibited substantial activation. In other epithelial cell lines, ABT-737 enhanced the cytotoxicity of PE-related immunotoxins by as much as 20-fold, but did not enhance diphtheria toxin or cycloheximide. Because PE translocates to the cytosol via the endoplasmic reticulum (ER) and the other toxins do not, ABT-737-mediated effects on the ER were investigated. ABT-737 treatment stimulated increased levels of ER stress response factor, ATF4. Because of its activity in the ER, ABT-737 might be particularly well suited for enhancing the activity of immunotoxins that translocate from the ER to the cell cytosol.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943340 | PMC |
| http://dx.doi.org/10.1158/1535-7163.MCT-10-0257 | DOI Listing |
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