Table 1 Current development of glutamine metabolism inhibition in treating cancer

Glutamine depletion

No specific glutamine depleting agent available, L-asparaginase acts as both L-glutamine and L-asparagine depleting agent (more detailed discussion in “Asparagine starvation”)

1. Clinical use in treating specific hematologic malignancies, glutamine depletion considered as an off-target effect (Anti-cancer efficacy of L-asparaginase to be discussed in the part of L-asparagine depletion)

[37, 48]

2. Glutamine depletion by methionine-L-sulfoximine suppressed sarcoma growth in vitro and HCC growth in vivo (subcutaneous (s.c) athymic mouse model)

Glutamine transporter inhibition

Specific inhibitor not yet available, benzylserine may inhibit one of the glutamine transporter SLC1A5

Benzylserine inhibited prostate cancer in vitro and in vivo (s.c. athymic mouse model)

[52]

Glutaminase inhibition

CB-839 (Glutaminase-1 specific)

1. Anti-proliferative effect on selected breast cancer cells in vitro and in vivo (s.c athymic mouse model), both as single agent or in combination with paclitaxel

[41, 62, 160, 161]

2. CB-839 synergizes with erlotinib to induce apoptosis in EGFR-mutated non-small cell lung cancer in vitro and reduced tumor growth in vivo (s.c. SCID mouse model)

3. CB-839 synergizes with Bcl-2 inhibitor ABT-199 in killing AML blasts in vitro and in vivo (NOD/SCID γleukemic mouse model)

4. CB-839 synergizes with carfilzomib in killing proteasome inhibitor resistant myeloma cell lines in vitro

BPTES (Glutaminase-1 specific)

1. Growth suppression in glioma cells with IDH-mutation in vitro

[53, 55, 58]

2. Growth suppression in acute myeloid leukemia cells with IDH-mutation in vitro

3. Caused lymphoma cell death in vitro

4. Prolonged mice survival in subcutaneous HCC and lymphoma model (s.c athymic mouse models)

BPTES nanoparticle

1. Intravenous BPTES-NP injection caused drug concentration in pancreatic cancer cells in vivo (orthotopic athymic mouse model)

[61]

2. BPTES-NP significantly reduced G2/M/S cycling cells but not hypoxic cells in vivo.

3. BPTES-NP combined with metformin could enhance tumor suppression in vivo by simultaneous inhibition of glucose and glutamine metabolism.

DON (Target glutaminase-1, may also target glutamine fructose-6-phosphate amidotransferase)

DON: 1. Suppressed growth in colorectal cancer cells in vitro

[36, 162]

2. Suppressed the growth and metastasis of subcutaneously implanted athymic mouse brain tumor

Alkyl benzoquinones, (Glutaminase-2 specific inhibitor)

Reduced proliferation and anchorage-independent colony formation and induce autophagy in liver cancer cells in vitro

[40]

968 (Glutaminase-1 specific)

1.Inhibited growth of oncogenic fibroblast, breast cancer and lymphoma cell lines in vitro through inhibition of glutaminase

[54, 56, 57, 59, 163]

2. Inhibited lymphoma growth in vivo (s.c. implanted lymphoma cell line in SCID mice)

3. Induced G1 phase cell cycle arrest, cellular stress and apoptosis and sensitized cells to anti-proliferative effect of paclitaxel in human ovarian cancer cell lines in vitro

4. Inhibited migration, proliferation and autophagy in non-small cell lung cancer in vitro, 968 combined with CQ further enhanced cell growth

5. Reduced the reactive oxygen species elimination capacity to potentiate the cytotoxicity induced by dihydroartmesinin in HCC in vitro