Abstract | PURPOSE: EXPERIMENTAL DESIGN: RESULTS: In two pancreatic cancer cell lines, immunotoxin treatment inhibited protein synthesis but did not produce significant cell death. The resistant lines had low levels of the proapoptotic protein Bak. Increasing Bak expression enhanced the sensitivity to immunotoxins, whereas Bak knockdown diminished it. We also found that combining immunotoxin with TRAIL or HGS-ETR2 caused synergistic cell death, and together triggered caspase-8 recruitment and activation, Bid cleavage and Bax activation. Combining SS1P with HGS-ETR2 also acted synergistically to decrease tumor burden in a mouse model. CONCLUSION: Our data show that low Bak can cause cancer cells to be resistant to immunotoxin treatment and that combining immunotoxin with TRAIL or a TRAIL agonist antibody can overcome resistance.
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Authors | Xing Du, Laiman Xiang, Crystal Mackall, Ira Pastan |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 17
Issue 18
Pg. 5926-34
(Sep 15 2011)
ISSN: 1557-3265 [Electronic] United States |
PMID | 21813632
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
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Copyright | ©2011 AACR. |
Chemical References |
- Antibodies, Monoclonal
- CASP8 and FADD-Like Apoptosis Regulating Protein
- CFLAR protein, human
- GPI-Linked Proteins
- Immunotoxins
- Msln protein, mouse
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- SS1(dsFv)PE38
- bcl-2 Homologous Antagonist-Killer Protein
- lexatumumab
- Mesothelin
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Topics |
- Animals
- Antibodies, Monoclonal
(therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Apoptosis
(drug effects)
- CASP8 and FADD-Like Apoptosis Regulating Protein
(metabolism)
- Cell Death
(drug effects)
- Cell Line, Tumor
- Disease Models, Animal
- Drug Resistance, Neoplasm
(drug effects)
- Drug Synergism
- GPI-Linked Proteins
(antagonists & inhibitors)
- HCT116 Cells
- HeLa Cells
- Humans
- Immunotoxins
(therapeutic use)
- Mesothelin
- Mice
- Mice, Nude
- Mitochondria
(drug effects, metabolism)
- Pancreatic Neoplasms
(drug therapy, metabolism)
- Protein Biosynthesis
(drug effects)
- Receptors, TNF-Related Apoptosis-Inducing Ligand
(agonists)
- Xenograft Model Antitumor Assays
- bcl-2 Homologous Antagonist-Killer Protein
(metabolism)
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