Arginine deprivation as an anticancer
therapy has historically been met with limited success. The development of
pegylated arginine deiminase (ADI-PEG20) has renewed interest in
arginine deprivation for the treatment of some
cancers. The efficacy of
ADI-PEG20 is directly correlated with
argininosuccinate synthetase (
ASS) deficiency. CWR22Rv1
prostate cancer cells do not express ASS, the rate-limiting
enzyme in
arginine synthesis, and are susceptible to
ADI-PEG20 in vitro. Interestingly, apoptosis by 0.3 microg/mL
ADI-PEG20 occurs 96 hours posttreatment and is
caspase independent. The effect of
ADI-PEG20 in vivo reveals reduced
tumor activity by micropositron emission tomography as well as reduced
tumor growth as a monotherapy and in combination with
docetaxel against CWR22Rv1 mouse xenografts. In addition, we show autophagy is induced by single
amino acid depletion by
ADI-PEG20. Here, autophagy is an early event that is detected within 1 to 4 hours of 0.3 microg/mL
ADI-PEG20 treatment and is an initial protective response to
ADI-PEG20 in CWR22Rv1 cells. Significantly, the inhibition of autophagy by
chloroquine and
Beclin1 siRNA knockdown enhances and accelerates ADI-PEG20-induced cell death. PC3 cells, which express reduced ASS, also undergo autophagy and are responsive to autophagy inhibition and
ADI-PEG20 treatment. In contrast, LNCaP cells highly express ASS and are therefore resistant to both
ADI-PEG20 and autophagic inhibition. These data point to an interrelationship among
ASS deficiency, autophagy, and cell death by
ADI-PEG20. Finally, a tissue microarray of 88 prostate
tumor samples lacked expression of ASS, indicating
ADI-PEG20 is a potential novel
therapy for the treatment of
prostate cancer