Background
Responses of cancer cells to amino acid starvation and the molecular mechanisms involved
Glutamine metabolism inhibition as an anti-cancer strategy
The role of glutamine in human body
Research targeting on glutamine metabolism inhibition in cancer treatment
Glutaminase inhibitor resistance and ways to enhance the efficacy for cancer treatment
Approach | Drug used | Cancer type tested and progress | Reference |
---|---|---|---|
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) | |
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 | |
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 | ||
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 | ||
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 | ||
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 |
Asparagine starvation as an anti-cancer strategy
The role of asparagine in human body
Research progress of L-asparaginase in cancer treatment
L-asparaginase resistance
Side effects of L-asparaginase and possible solutions
Arginine starvation as an anti-cancer strategy
The role of arginine in human body
The role of arginine derivatives in cancer
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) | |
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 | |
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) | |
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] |
Cancer type tested | Progress | References |
---|---|---|
Hepatocellular carcinoma (HCC) | 1. Suppressed HCC cell growth and induced apoptosis in vitro | |
2. Suppressed OTC-deficient tumor growth in athymic nude mice | ||
Acute myeloid leukemia (AML) | 1. Induced necrotic cell death in AML cell lines and some AML patient samples in vitro and in vivo (implantation of HL-60 cell line in to NOD/SCID γ mice through tail vein) | [154] |
2. Peg-arg I + cytarabine enhanced cytotoxicity in AML cell lines and AML patient samples in vitro | ||
Acute lymphoblastic leukemia (ALL) | 1. Induced apoptosis in T-lineage ALL (T-ALL) cell lines in vitro | |
2. Peg-arg I + cytarabine therapy induced T- ALL cell apoptosis in vivo (Peg-arg I monotherapy did not prolong the survival of T-ALL bearing in NOD-SCID mice) | ||
3. MSCs protected T-lineage ALL cell lines from peg-arg I cytotoxicity via soluble factors in vitro, pre-treating MSCs with vincristine may suppress such stromal protection | ||
4. eIF2α phosphorylation sensitized T-ALL cells to peg-arg I cytotoxicity in NOD-SCID mice | ||
Glioblastoma | 1. Induced ASS1-dependent non-apoptotic cell death which may be enhanced by autophagy inhibitor CQ in glioblastoma cell lines in vitro | [174] |
Melanoma | 1. Induced S and G2/M phases cell cycle arrest and apoptosis in melanoma cell line A375 in vitro | [175] |
2. Suppressed s.c. implanted melanoma in athymic nude mice | ||
Prostate cancer | Induced autophagic cell death in OTC-ve cells in vitro | [176] |
Pancreatic cancer | 1. Induced apoptosis in pancreatic cancer cell line Panc-1 in vitro | [172] |
2. Suppressed tumor growth in a s.c. implanted pancreatic cancer in athymic mice model | ||
Mesothelioma | 1. Suppressed growth of different cell lines in vitro and in vivo (s.c. implanted mesothelioma in athymic nude mouse model) | [148] |
2.Induced apoptosis and G1 arrest in mesothelioma cells in vivo | ||
3. Peg-arg I, cispatin and premetrexed did not show synergistic effect against mesothelioma growth in vivo | ||
4. Peg-arg I depleted serum and intratumoral arginine, and was internalized in mesothelioma cells in vivo |