Medhi Wangpaichitr1, Chunjing Wu2, Gregory Bigford3, George Theodoropoulos2, Min You4, Ying Ying Li5, Javier Verona-Santos4, Lynn G Feun5, Dao M Nguyen4, Niramol Savaraj6. 1. Miami VA Healthcare System, Department of Veterans Affairs, Miami, FL, U.S.A. Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, U.S.A. mwangpaichitr@med.miami.edu. 2. Miami VA Healthcare System, Department of Veterans Affairs, Miami, FL, U.S.A. 3. The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, FL, U.S.A. 4. Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, U.S.A. 5. Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, U.S.A. 6. Miami VA Healthcare System, Department of Veterans Affairs, Miami, FL, U.S.A. Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
Abstract
UNLABELLED: In the present study we present data to show that certain tumor cells including malignant pleural mesothelioma (MPM) cells do not express argininosuccinate synthetase (ASS), and thus are unable to synthesize arginine from citrulline. Exposure of these ASS-negative cells to the arginine degrading enzyme, arginine deiminase (ADI-PEG20), for 72 h results in significant increases in cleaved caspase-3. Importantly, this apoptotic signal is further strengthened by the addition of TNF-related apoptosis-inducing ligand (TRAIL). Using flow cytometry, we showed that the combination treatment (ADI-PEG20 at 50 ng/ml and TRAIL at 10 ng/ml) for 24 h resulted in profound cell death with 67% of cells positive for caspase-3 activity, while ADI-PEG20 alone or TRAIL alone resulted in only 10-15% cell death. This positive amplification loop is mediated through the cleavage of proapototic protein "BID". CONCLUSION: Our work represents a new strategy for treating patients with malignant pleural mesothelioma using targeted molecular therapeutics based on selected tumor markers, thus avoiding the use of potentially cytotoxic chemotherapy. Copyright
UNLABELLED: In the present study we present data to show that certain tumor cells including malignant pleural mesothelioma (MPM) cells do not express argininosuccinate synthetase (ASS), and thus are unable to synthesize arginine from citrulline. Exposure of these ASS-negative cells to the arginine degrading enzyme, arginine deiminase (ADI-PEG20), for 72 h results in significant increases in cleaved caspase-3. Importantly, this apoptotic signal is further strengthened by the addition of TNF-related apoptosis-inducing ligand (TRAIL). Using flow cytometry, we showed that the combination treatment (ADI-PEG20 at 50 ng/ml and TRAIL at 10 ng/ml) for 24 h resulted in profound cell death with 67% of cells positive for caspase-3 activity, while ADI-PEG20 alone or TRAIL alone resulted in only 10-15% cell death. This positive amplification loop is mediated through the cleavage of proapototic protein "BID". CONCLUSION: Our work represents a new strategy for treating patients with malignant pleural mesothelioma using targeted molecular therapeutics based on selected tumor markers, thus avoiding the use of potentially cytotoxic chemotherapy. Copyright
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