Co-application of canavanine and irradiation uncouples anticancer potential of arginine deprivation from citrulline availability

Kurlishchuk, Yuliya; Vynnytska-Myronovska, Bozhena; Grosse‐Gehling, Philipp; Bobak, Yaroslav; Manig, Friederike; Chen, Oleg; Merker, Sebastian R.; Henle, Thomas; Löck, Steffen; Stange, Daniel E.; Stasyk, Oleh; Kunz-Schughart, Leoni A.

doi:10.18632/oncotarget.12320

Cited by 9 publications

(21 citation statements)

References 60 publications

(96 reference statements)

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“…Arginine deprivation is an emerging approach to treat selected tumors . As a targeted anticancer therapy, the efficiency of arginine deprivation is related to ASS1 and OTC expression, two critical enzymes in the urea cycle .…”

Section: Discussionmentioning

confidence: 99%

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Recombinant human arginase induces apoptosis through oxidative stress and cell cycle arrest in small cell lung cancer

Lam

Cheng³

et al. 2018

Cancer Science

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Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer cases. Small cell lung cancer is characterized by frequent relapse, and current treatments lack tumor specificity. Arginine is a non‐essential amino acid for human normal cells but critical to some tumor cells that cannot synthesize arginine. Therefore, arginine deprivation has become a potential therapeutic option for selected tumors. BCT‐100 is a pegylated arginase that has documented anticancer activity in arginine auxotrophic tumors, such as melanoma, hepatocellular carcinoma, and acute myeloid leukemia. One of the resistance mechanisms to arginase treatment is overexpression of argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC), two important enzymes in the urea cycle. We selected 9 SCLC and 1 non‐small cell lung carcinoma cell lines to determine the growth inhibition effects of BCT‐100 and established that cell lines with low expression of ASS1 and OTC are relatively sensitive to BCT‐100 treatment. Knocking down OTC in a H841 cell line could potentiate its sensitivity to BCT‐100 treatment. Arginine concentration was sharply decreased, accompanied by apoptosis through oxidative stress as well as G1 cell cycle arrest. In addition, BCT‐100 showed an anticancer effect on H446 and H510A xenograft models by lowering arginine levels and inducing apoptosis.

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Section: Discussionmentioning

confidence: 99%

“…Arginine deprivation is an emerging approach to treat selected tumors. 21 As a targeted anticancer therapy, the efficiency of arginine deprivation is related to ASS1 and OTC expression, two critical enzymes in the urea cycle. 22 We purchased 9 commercially available SCLC cell lines from ATCC without selection of basal expression of ASS1 or OTC.…”

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confidence: 99%

Recombinant human arginase induces apoptosis through oxidative stress and cell cycle arrest in small cell lung cancer

Lam

Cheng³

et al. 2018

Cancer Science

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“…For more details, see ref. 27. PI was also applied for static DNA analyses using the handling protocol from (28).…”

Section: Static and Dynamic Cell-cycle Analysesmentioning

confidence: 99%

“…Dynamic cell-cycle analysis using a 1-hour EdU pulse was applied because (i) a phase-independent cell-cycle arrest by ADT was described recently in colorectal cancer cells (27) and (ii) the changes seen in the DNA histograms of GBM cultures did not fully explain their growth arrest. Fig.…”

Section: Mechanism Of Radiosensitization By Adt In Gbm Cells Remainsmentioning

confidence: 99%

Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization

Hinrichs

Ingargiola

Käubler

et al. 2018

Molecular Cancer Therapeutics

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Tumor cells-even if nonauxotrophic-are often highly sensitive to arginine deficiency. We hypothesized that arginine deprivation therapy (ADT) if combined with irradiation could be a new treatment strategy for glioblastoma (GBM) patients because systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle study was performed with ADT being mimicked by application of recombinant human arginase or arginine-free diets. ADT inhibited two-dimensional (2-D) growth and cell-cycle progression, and reduced growth recovery after completion of treatment in four different GBM cell line models. Cells were less susceptible to ADT alone in the presence of citrulline and in a three-dimensional (3-D) environment. Migration and 3-D invasion were not unfavorably affected. However, ADT caused a significant radiosensitization that was more pronounced in a GBM cell model with p53 loss of function as compared with its p53-wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase or argininosuccinate lyase protein expression and not abrogated by the presence of citrulline. The radiosensitizing potential was maintained or even more distinguishable in a 3-D environment as verified in p53-knockdown and p53-wildtype U87-MG cells via a 60-day spheroid control probability assay. Although the underlying mechanism is still ambiguous, the observation of ADT-induced radiosensitization is of great clinical interest, in particular for patients with GBM showing high radioresistance and/or p53 loss of function.

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“…Recently, we demonstrated a strong synergistic effect when ADT was combined with low concentrations of Cav [9][10][11][12][13]. The natural Arg analog Canavanine (Cav) can effectively compete with Arg for arginyl tRNA synthase and incorporates into cellular proteins, thereby causing conformational changes and impairing enzymatic activities and functions [14].…”

Section: Introductionmentioning

confidence: 99%

Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells

Chen

Manig

Lehmann

et al. 2020

Cell. Mol. Life Sci.

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Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy.

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Co-application of canavanine and irradiation uncouples anticancer potential of arginine deprivation from citrulline availability

Cited by 9 publications

References 60 publications

Recombinant human arginase induces apoptosis through oxidative stress and cell cycle arrest in small cell lung cancer

Recombinant human arginase induces apoptosis through oxidative stress and cell cycle arrest in small cell lung cancer

Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization

Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells

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