The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma

Thongkum, Angkana; Wu, Chunjing; Li, Ying Ying; Wangpaichitr, Medhi; Navasumrit, Panida; Parnlob, Varabhorn; Sricharunrat, Thaniya; Bhudhisawasdi, Vajarabhongsa; Ruchirawat, Mathuros; Savaraj, Niramol

doi:10.3390/ijms18061175

Cited by 25 publications

(16 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its anti-angiogenic activity suggests that ADI could become a novel anti-cancer drug targeting neovascularization-related tumors. In other studies, ADI-PEG20 treatment downregulated thymidylate synthase and interfered with pyrimidine synthesis [65,78]. This is of particular relevance for combination approaches using the standard chemotherapeutic drug 5-Fluorouracil (5-FU).…”

Section: Strategies To Improve Adi-based Therapymentioning

confidence: 99%

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches.

show abstract

Section: Strategies To Improve Adi-based Therapymentioning

confidence: 99%

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…We and others proposed that anticancer therapy based on single-amino-acid arginine deprivation that utilizes recombinant arginine-degrading enzymes could be applied as an antiglioblastoma treatment [ 1 , 24 , 25 ]. This metabolic approach has already achieved significant progress in cell culture and animal studies, and in clinical trials aimed at a growing number of cancer types [ 68 ]. Although the feasibility of this approach for the treatment of various cancers, primarily those with defects in arginine anabolism, has been demonstrated [ 67 , 68 ], we have found that the strong antitumor effect of arginine starvation observed in standard in vitro monolayer cell cultures does not fully translate into 3D cultures [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

“…This metabolic approach has already achieved significant progress in cell culture and animal studies, and in clinical trials aimed at a growing number of cancer types [ 68 ]. Although the feasibility of this approach for the treatment of various cancers, primarily those with defects in arginine anabolism, has been demonstrated [ 67 , 68 ], we have found that the strong antitumor effect of arginine starvation observed in standard in vitro monolayer cell cultures does not fully translate into 3D cultures [ 69 ]. We and others proposed, therefore, that rationally designed combinational modalities are needed for the approach to successfully proceed into clinical use [ 1 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms

Karatsai

Shliaha

Jensen

et al. 2020

Cells

View full text Add to dashboard Cite

Glioblastomas are the most frequent and aggressive form of primary brain tumors with no efficient cure. However, they often exhibit specific metabolic shifts that include deficiency in the biosynthesis of and dependence on certain exogenous amino acids. Here, we evaluated, in vitro, a novel combinatory antiglioblastoma approach based on arginine deprivation and canavanine, an arginine analogue of plant origin, using two human glioblastoma cell models, U251MG and U87MG. The combinatory treatment profoundly affected cell viability, morphology, motility and adhesion, destabilizing the cytoskeleton and mitochondrial network, and induced apoptotic cell death. Importantly, the effects were selective toward glioblastoma cells, as they were not pronounced for primary rat glial cells. At the molecular level, canavanine inhibited prosurvival kinases such as FAK, Akt and AMPK. Its effects on protein synthesis and stress response pathways were more complex and dependent on exposure time. We directly observed canavanine incorporation into nascent proteins by using quantitative proteomics. Although canavanine in the absence of arginine readily incorporated into polypeptides, no motif preference for such incorporation was observed. Our findings provide a strong rationale for further developing the proposed modality based on canavanine and arginine deprivation as a potential antiglioblastoma metabolic therapy independent of the blood–brain barrier.

show abstract

“…Similar to this finding, it has been shown that in human pancreatic cancer ( 26 ), HCC, myxofibrosarcoma and bladder cancer, decreased ASS expression correlated with histopathological grading ( 27 ). For instance, a 1.29-fold reduction of ASS expression in tumor cells of HCC specimens was associated with poor tumor differentiation ( 21 ). However, there was no association found between ASS expression and histopathological characteristics of tumors in a cohort study of lung cancer patients ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…ASS expression in CCA specimens was classified as low or high according to a previous report ( 21 ). Briefly, IHC analysis of ASS and Ki-67 expression in CCA specimens was determined by HistoFAXS software Version 4.1 and viewed at 100× magnification.…”

Section: Methodsmentioning

confidence: 99%

Decreased argininosuccinate synthetase expression in Thai patients with cholangiocarcinoma and the effects of ADI‑PEG20 treatment in CCA cell lines

et al. 2018

Self Cite

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) is a severe cancer with poor prognosis. The aim of the present study was to explore the expression of argininosuccinate synthetase (ASS), as well as the possibility of using pegylated arginine deiminase (ADI-PEG20) for the treatment of CCA. ASS expression was determined in CCA specimens from 40 patients in Thailand. Immunohistochemical detection of ASS and determination of the proliferative index, Ki-67, were carried out in paraffin-embedded sections of these specimens, as well as in two CCA cell lines, HuCCA and RmCCA-1, derived from CCA samples from patients in Thailand. In total, ~45% of the CCA specimens had low ASS expression, and the level of expression was significantly negatively associated with cell differentiation (P<0.05) and Ki-67 expression (P<0.05). The level of ASS expression in tumor cells was significantly lower than that in non-tumor cells (1.3-fold, P<0.05). The HuCCA cell line had significantly lower levels (P<0.05) of ASS expression at the mRNA and protein levels relative to those of normal human immortalized fibroblast cells (BJ-1). By contrast, the RmCCA-1 cell line showed no significant difference. In addition, the effects of ADI-PEG20 on growth inhibition, apoptosis and cell cycle arrest were determined in HuCCA and RmCCA-1 cells. ADI-PEG20 treatment reduced cell viability and cell proliferation in the two CCA cell lines, though it had no effect in immortalized BJ-1 cells. Furthermore, ADI-PEG20 treatment significantly increased G0/G1 cell cycle arrest in HuCCA, though not in RmCCA-1 cells. ASS silencing in the RmCCA-1 cell line significantly enhanced its sensitivity to ADI-PEG20 treatment. Results from the in vitro study demonstrated that ADI-PEG20 has antitumor activity against CCA with low ASS expression.

show abstract

The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma

Cited by 25 publications

References 43 publications

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms

Decreased argininosuccinate synthetase expression in Thai patients with cholangiocarcinoma and the effects of ADI‑PEG20 treatment in CCA cell lines

Contact Info

Product

Resources

About