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Preclinical Studies in Pancreatic Cancer and Melanoma Demonstrated ADI-PEG 20 Works Synergistically With Inhibitors of Autophagy
Date:4/11/2011

d caspase-dependent cell death as well as autophagy. ChQ at low doses inhibited autophagy induced by ADI-PEG 20, but increased cell death. In xenografts, addition of ChQ to a sub-therapeutic dose of ADI-PEG 20 increased tumor suppression, decreased autophagy and increased cell death compared to either treatment alone. Arginine deprivation by ADI-PEG 20 induces autophagy and cell death in cell lines deficient in ASS1. Autophagy appears to play a protective role, and its inactivation by ChQ enhances tumor suppression. Combining ChQ with ADI-PEG 20 in pancreatic cancer may increase the cell death induced by ADI-PEG 20 by blocking ADI-PEG 20-induced autophagy.

TRAIL enhances cytotoxicity of arginine depletion therapy in argininosuccinate synthetase-negative melanoma cells through interruption of autophagy via activation of caspases

Min You et. al. (AACR Abstract # 4096)

Melanomas that do not express the gene that codes for ASS (ASS1) cannot make arginine from citrulline; thus arginine depletion caused by ADI-PEG 20 results in growth inhibition and eventually leads to cell death. However, autophagy does take place during arginine deprivation in melanoma which prevents death in some melanoma cells. During this period, certain melanoma cells can turn on the ASS1 gene and hence become resistant to ADI-PEG 20. It has previously been shown that combining tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with ADI-PEG 20 can accelerate the cell death (apoptosis) process and hence greatly enhance cytotoxicity. In this study, further data from combination treatment confirm that the enhancement effect of the combination needs the participation of both the extrinsic and intrinsic pathways of apoptosis. This finding suggests that the combination treatment turns off the autophagic process during arginine deprivation, possibly through caspase activation, and allows the apoptotic process to take place. Overall, these findin
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