Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas

Maletzki, Claudia; Rosche, Yvonne; Riess, Christin; Scholz, Aline; William, Doreen; Classen, Carl Friedrich; Kreikemeyer, Bernd; Linnebacher, Michael; Fiedler, Tomas

doi:10.1016/j.cbi.2017.10.007

Cited by 16 publications

(33 citation statements)

References 34 publications

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“…Additional genes OTC and arginase I were almost entirely downregulated in this cohort, whereas carbamoyl phosphate synthase I was expressed by all cell lines [31]. A reduced transcription level of one of those genes was seen in particular in cells with normal ASS1/ASL expression [31]. Supporting these findings, a recent report described significant downregulation of OTC in pediatric sarcomas and brain tumors with normal ASS1 expression [32].…”

Section: Arginine Auxotrophy In Human Malignanciessupporting

confidence: 77%

“…In our own studies on patient-derived GBM cell lines, comparable results were obtained, with reduced ASL mRNA levels in half of the examined cases (12 in total) [30]. Additional genes OTC and arginase I were almost entirely downregulated in this cohort, whereas carbamoyl phosphate synthase I was expressed by all cell lines [31]. A reduced transcription level of one of those genes was seen in particular in cells with normal ASS1/ASL expression [31].…”

Section: Arginine Auxotrophy In Human Malignanciessupporting

confidence: 72%

“…3). This is accompanied by cell cycle alterations (G 1 or S phase arrest), as proven for pancreatic and breast cancer as well as GBM cells [30,31,71].…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 85%

“…Cells routinely express senescence-associated β-galactosidase, detectable at pH 6.0 with the artificial substrate X-gal, as well as several inflammatory cytokines (interleukin-1 (IL-1), IL-6, and IL-8) and signaling molecules (p16 INK4a , in the case of wildtype CDKN2A gene). So far, senescence induction was only confirmed in GBM cells [31]. These tumor cells show intrinsic apoptosis resistance.…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 98%

“…In our own studies, chronic arginine starvation of apoptosis-resistant GBM either in vitro (= eight repetitive cycles) or in vivo (= six peritumoral injections) with S. pyogenes ADI boosted cell death. In vitro cultured cells treated for a long term had elevated numbers of senescent cells, most likely a result of prolonged and durable cellular stress [31].…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

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

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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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.

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Section: Arginine Auxotrophy In Human Malignanciessupporting

confidence: 77%

Section: Arginine Auxotrophy In Human Malignanciessupporting

confidence: 72%

“…3). This is accompanied by cell cycle alterations (G 1 or S phase arrest), as proven for pancreatic and breast cancer as well as GBM cells [30,31,71].…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 85%

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 98%

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

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

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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PEGylation increases antitumoral activity of arginine deiminase of Streptococcus pyogenes

Schwarz

Zitzow

Fiebig

et al. 2021

Appl Microbiol Biotechnol

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Arginine auxotrophy is a metabolic defect that renders tumor cells vulnerable towards arginine-depleting substances, such as arginine deiminase (ADI) from Streptococcus pyogenes (SpyADI). Previously, we confirmed SpyADI susceptibility on patient-derived glioblastoma multiforme (GBM) models in vitro and in vivo. For application in patients, serum half-life of the enzyme has to be increased and immunogenicity needs to be reduced. For this purpose, we conjugated the S. pyogenes-derived SpyADI with 20 kDa polyethylene glycol (PEG20) moieties, achieving a PEGylation of seven to eight of the 26 accessible primary amines of the SpyADI. The PEGylation reduced the overall activity of the enzyme by about 50% without affecting the Michaelis constant for arginine. PEGylation did not increase serum stability of SpyADI in vitro, but led to a longer-lasting reduction of plasma arginine levels in mice. Furthermore, SpyADI-PEG20 showed a higher antitumoral capacity towards GBM cells in vitro than the native enzyme. Key points • PEGylation has no effect on the affinity of SpyADI for arginine • PEGylation increases the antitumoral effects of SpyADI on GBM in vitro • PEGylation prolongs plasma arginine depletion by SpyADI in mice

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Cellular senescence in glioma

et al. 2023

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Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas

Cited by 16 publications

References 34 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

PEGylation increases antitumoral activity of arginine deiminase of Streptococcus pyogenes

Cellular senescence in glioma

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