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Table 2 Current progress of pre-clinical studies of ADI-PEG20 in treating cancer

From: Drug-induced amino acid deprivation as strategy for cancer therapy

Cancer type tested

Progress

References

Hepatocellular carcinoma (HCC)

1. Decreased HCC cell viability in vitro

[13]

2. Suppressed tumor growth and prolonged survival of engrafted.c. implanted tumor-bearing SCID mice

3. ASS1 + ve and OTC + ve HCC cells are resistant to ADI.

Melanoma

1. Decreased melanoma cell viability in vitro

[13]

2. Suppressed tumor growth and prolonged survival of s.c. implanted tumor-bearing athymic nude mice

Small cell lung cancer

1. Induced autophagy and cell death in ASS1-ve cell in vitro (about 50% of samples tested in the study were ASS1-ve)

[164]

2. Suppressed growth of s.c. implanted tumor in athymic nude mice

Glioblastoma

1. Induced autophagy and caspase independent cell death in ASS1-ve cell lines and clinical samples (approximately 30% glioblastoma samples tested in the study are ASS1-ve)

[165]

2. Autophagy inhibitor chlorquine accelerated ADI-PEG20 induced cell death in vitro

Pancreatic cancer

1. Inhibited growth and induced apoptosis of ASS1-ve pancreatic cancer cell lines in vitro (about 80% pancreatic cancer samples tested in the study were ASS1-ve)

[166, 167]

2. Suppressed growth of subcutaneously implanted tumor in athymic nude mice.

3. ADI-PEG20 + gemcitabine showed enhanced cell death in gemcitabine-resistant ASS1-ve pancreatic cell line compared to ADI-PEG20 or gemcitabine only groups in vitro

4. ADI-PEG20 + gemcitabine enhanced growth suppression in s.c. implanted gemcitabine-resistant ASS1-ve tumor in athymic nude mice.

Acute myeloid leukemia (AML)

1. Induced primary AML apoptosis in vitro

[137]

2. Reduced AML burden in NOD-SCID mice

3. ADI-PEG20 + cytarabine further enhanced AML clearance

Prostate cancer

1. Induced autophagy, mitochondrial dysfunction, DNA leakage and caspase-independent cell death in a prostate cancer cell line in vitro

[132, 168]

2. Autophagy inhibitor chloroquine enhanced and accelerated ADI-PEG20 induced prostate cancer cell death in vitro

3. ADI-PEG20 + docetaxel showed enhanced tumor suppression in s.c. implanted tumor in athymic nude mice

Bladder cancer

1. Induced caspase-independent apoptosis and autophagy in bladder cancer cell lines in vitro and reduced tumor growth and in vivo (s.c. implanted tumor in athymic nude mice)

[169, 170]

2. ASS1-ve due to methylation may be related poor prognosis clinically, and linked to invasion and enhanced invasion and proliferation in bladder cancer cells in vitro

3. Inhibited pyrimidine metabolism by reducing protein level of thymidylate synthase, dihydro-folate reductase and thymidine kinase 1 and enhanced cytotoxicity in ASS1-methylated bladder cancer cell lines in vitro and in vivo (s.c. implanted tumor in CD1 nude mice)

Breast cancer

Induced mitochondrial damage and autophagy-dependent cell death in ASS1-ve breast cancer cell in vitro

[171]